Combined parasympathetic stimulation and drug therapy

ABSTRACT

A method is provided for treating a subject, including applying a current to a site of the subject selected from the list consisting of: a vagus nerve of the subject, an epicardial fat pad of the subject, a pulmonary vein of the subject, a carotid artery of the subject, a carotid sinus of the subject, a vena cava vein of the subject, and an internal jugular vein of the subject. The method also includes configuring the current so as to treat a condition of the subject selected from the list consisting of: an autoimmune disease, an autoimmune inflammatory disease, multiple sclerosis, encephalitis, myelitis, immune-mediated neuropathy, myositis, dermatomyositis, polymyositis, inclusion body myositis, inflammatory demyelinating polyradiculoneuropathy, Guillain Barre syndrome, myasthenia gravis, inflammation of the nervous system, inflammatory bowel disease, Crohn&#39;s disease, ulcerative colitis, SLE (systemic lupus erythematosus), rheumatoid arthritis, vasculitis, polyarteritis nodosa, Sjogren syndrome, mixed connective tissue disease, glomerulonephritis, thyroid autoimmune disease, sepsis, meningitis, a bacterial infection, a viral infection, a fungal infection, sarcoidosis, hepatitis, and portal vein hypertension.

CROSS-REFERENCES TO RELATED APPLICATIONS

This application is a continuation of U.S. Ser. No. 10/866,601, filedJun. 10, 2004, which claims benefit from U.S. Provisional ApplicationNo. 60/478,576, filed Jun. 13, 2003, and claims priority of PCTInternational Application No. PCT/IL2004/000495, filed Jun. 10, 2004,which designates the United States of America, the content of each ofwhich is hereby incorporated herein by reference into this application.

FIELD OF THE INVENTION

The present invention relates generally to treating patients byapplication of electrical signals to selected tissue, and specificallyto methods and apparatus for stimulating tissue for treating patientssuffering from conditions such as atrial fibrillation, heart failure, orhypertension.

BACKGROUND OF THE INVENTION

The use of nerve stimulation for treating and controlling a variety ofmedical, psychiatric, and neurological disorders has seen significantgrowth over the last several decades, including for treatment of heartconditions. In particular, stimulation of the vagus nerve (the tenthcranial nerve, and part of the parasympathetic nervous system) has beenthe subject of considerable research. The vagus nerve is composed ofsomatic and visceral afferents (inward conducting nerve fibers, whichconvey impulses toward the brain) and efferents (outward conductingnerve fibers, which convey impulses to an effector to regulate activitysuch as muscle contraction or glandular secretion).

The rate of the heart is restrained in part by parasympatheticstimulation from the right and left vagus nerves. Low vagal nerveactivity is considered to be related to various arrhythmias, includingtachycardia, ventricular accelerated rhythm, and rapid atrialfibrillation. By artificially stimulating the vagus nerves, it ispossible to slow the heart, allowing the heart to more completely relaxand the ventricles to experience increased filling. With largerdiastolic volumes, the heart may beat more efficiently because it mayexpend less energy to overcome the myocardial viscosity and elasticforces of the heart with each beat.

Stimulation of the vagus nerve has been proposed as a method fortreating various heart conditions, including atrial fibrillation andheart failure. Atrial fibrillation is a condition in which the atria ofthe heart fail to continuously contract in synchrony with the ventriclesof the heart. During fibrillation, the atria undergo rapid andunorganized electrical depolarization, so that no contractile force isproduced. The ventricles, which normally receive contraction signalsfrom the atria (through the atrioventricular (AV) node), are inundatedwith signals, typically resulting in a rapid and irregular ventricularrate. Because of this rapid and irregular rate, the patient suffers fromreduced cardiac output and/or a feeling of palpitations.

Current therapy for atrial fibrillation includes cardioversion and ratecontrol. Cardioversion is the conversion of the abnormal atrial rhythminto normal sinus rhythm. This conversion is generally achievedpharmacologically or electrically. Rate control therapy is used tocontrol the ventricular rate, while allowing the atria to continuefibrillation. This is generally achieved by slowing the conduction ofsignals through the AV node from the atria to the ventricles.

After cardioversion has been successfully performed, drug therapy issometimes indicated for sinus rhythm maintenance or ventricular ratecontrol (see Fuster et al., in their articles cited hereinbelow).Commonly used antiarrhythmic drugs for prophylactic maintenance of sinusrhythm include beta-blockers, amiodarone, disopyramide, dofetilide,flecainide, procainamide, propafenone, quinidine, and sotalol. Potentialadverse effects of these drugs include hypotension, bradycardia, QTprolongation, ventricular proarrhythmia (ventricular tachycardia,including torsades de pointes), postural hypotension, and GI complaints,such as diarrhea. For ventricular rate control, commonly used drugsinclude beta-blockers (e.g., esmolol), calcium channel antagonists(e.g., verapamil, diltiazem) and digoxin. Potential adverse effects ofthese drugs include hypotension, heart block, heart failure, andbradycardia.

Bilgutay et al., in “Vagal tuning: a new concept in the treatment ofsupraventricular arrhythmias, angina pectoris, and heart failure,” J.Thoracic Cardiovas. Surg. 56 (1):71-82, July, 1968, which isincorporated herein by reference, studied the use of apermanently-implanted device with electrodes to stimulate the rightvagus nerve for treatment of supraventricular arrhythmias, anginapectoris, and heart failure. Experiments were conducted to determineamplitudes, frequencies, wave shapes and pulse lengths of thestimulating current to achieve slowing of the heart rate. The authorsadditionally studied an external device, triggered by the R-wave of theelectrocardiogram (ECG) of the subject to provide stimulation only uponan achievement of a certain heart rate. They found that when a pulsatilecurrent with a frequency of ten pulses per second and 0.2 millisecondspulse duration was applied to the vagus nerve, the heart rate could bedecreased to half the resting rate while still preserving sinus rhythm.Low amplitude vagal stimulation was employed to control inducedtachycardias and ectopic beats. The authors further studied the use ofthe implanted device in conjunction with the administration of Isuprel,a sympathomimetic drug. They found that Isuprel retained its inotropiceffect of increasing contractility, while its chronotropic effect wascontrolled by the vagal stimulation: “An increased end diastolic volumebrought about by slowing of the heart rate by vagal tuning, coupled withincreased contractility of the heart induced by the inotropic effect ofIsuprel, appeared to increase the efficiency of cardiac performance” (p.79).

An article by Moreira et al., entitled, “Chronic rapid atrial pacing tomaintain atrial fibrillation: Use to permit control of ventricular ratein order to treat tachycardia induced cardiomyopathy,” Pacing ClinElectrophysiol, 12(5):761-775 (May 1989), which is incorporated hereinby reference, describes the acute induction of atrial fibrillation withrapid atrial pacing, and an associated reduction in ventricular ratewith digitalis therapy. Different treatment protocols are described toinduce and maintain atrial fibrillation, in order to bring a patientwith NYHA class III-IV congestive heart failure to a more moderate NYHAclass II.

An article by Preston et al., entitled, “Permanent rapid atrial pacingto control supraventricular tachycardia,” Pacing Clin Electrophysiol,2(3):331-334 (May 1979), which is incorporated herein by reference,describes a patient who had continuous supraventricular tachycardia witha ventricular rate of about 170. The arrhythmia was refractory to drugsand DC countershock, and did not convert with atrial pacing. Rapidatrial stimulation (pacing at 300-400/min) controlled the ventricularrate by simulating atrial fibrillation. This therapy was used on apermanent basis for more than five months.

U.S. Pat. No. 6,473,644 to Terry, Jr. et al., which is incorporatedherein by reference, describes a method for treating patients sufferingfrom heart failure to increase cardiac output, by stimulating ormodulating the vagus nerve with a sequence of substantiallyequally-spaced pulses by an implanted neurostimulator. The frequency ofthe stimulating pulses is adjusted until the patient's heart ratereaches a target rate within a relatively stable target rate range belowthe low end of the patient's customary resting heart rate.

US Patent Application Publication 2003/0040774 to Terry et al., which isincorporated herein by reference, describes a device for treatingpatients suffering from congestive heart failure. The device includes animplantable neurostimulator for stimulating the patient's vagus nerve ator above the cardiac branch with an electrical pulse waveform at astimulating rate sufficient to maintain the patient's heart beat at arate well below the patient's normal resting heart rate, therebyallowing rest and recovery of the heart muscle, to increase in coronaryblood flow, and/or growth of coronary capillaries. A metabolic needsensor detects the patient's current physical state and concomitantlysupplies a control signal to the neurostimulator to vary the stimulatingrate. If the detection indicates a state of rest, the neurostimulatorrate reduces the patient's heart rate below the patient's normal restingrate. If the detection indicates physical exertion, the neurostimulatorrate increases the patient's heart rate above the normal resting rate.

US Patent Publication 2003/0045909 to Gross et al., which is assigned tothe assignee of the present patent application and is incorporatedherein by reference, describes apparatus for treating a heart conditionof a subject, including an electrode device, which is adapted to becoupled to a vagus nerve of the subject. A control unit is adapted todrive the electrode device to apply to the vagus nerve a stimulatingcurrent, which is capable of inducing action potentials in a therapeuticdirection in a first set and a second set of nerve fibers of the vagusnerve. The control unit is also adapted to drive the electrode device toapply to the vagus nerve an inhibiting current, which is capable ofinhibiting the induced action potentials traveling in the therapeuticdirection in the second set of nerve fibers, the nerve fibers in thesecond set having generally larger diameters than the nerve fibers inthe first set.

The effect of vagal stimulation on heart rate and other aspects of heartfunction, including the relationship between the timing of vagalstimulation within the cardiac cycle and the induced effect on heartrate, has been studied in animals. For example, Zhang Y et al., in“Optimal ventricular rate slowing during atrial fibrillation by feedbackAV nodal-selective vagal stimulation,” Am J Physiol Heart Circ Physiol282:H1102-H1110 (2002), describe the application of selective vagalstimulation by varying the nerve stimulation intensity, in order toachieve graded slowing of heart rate. This article is incorporatedherein by reference.

The following articles and book, which are incorporated herein byreference, may be of interest:

Levy M N et al., in “Parasympathetic Control of the Heart,” NervousControl of Vascular Function, Randall W C ed., Oxford University Press(1984)

Levy M N et al. ed., Vagal Control of the Heart: Experimental Basis andClinical Implications (The Bakken Research Center Series Volume 7),Futura Publishing Company, Inc., Armonk, N.Y. (1993)

Randall W C ed., Neural Regulation of the Heart, Oxford University Press(1977), particularly pages 100-106.

Armour J A et al. eds., Neurocardiology, Oxford University Press (1994)

Perez M G et al., “Effect of stimulating non-myelinated vagal axon onatrio-ventricular conduction and left ventricular function inanaesthetized rabbits,” Auton Neurosco 86 (2001)

Jones, J F X et al., “Heart rate responses to selective stimulation ofcardiac vagal C fibres in anaesthetized cats, rats and rabbits,” JPhysiol 489 (Pt 1):203-14 (1995)

Wallick D W et al., “Effects of ouabain and vagal stimulation on heartrate in the dog,” Cardiovasc. Res., 18(2):75-9 (1984)

Martin P J et al., “Phasic effects of repetitive vagal stimulation onatrial contraction,” Circ. Res. 52(6):657-63 (1983)

Wallick D W et al., “Effects of repetitive bursts of vagal activity onatrioventricular junctional rate in dogs,” Am J Physiol 237(3):H275-81(1979)

Fuster V and Ryden L E et al., “ACC/AHA/ESC PracticeGuidelines—Executive Summary,” J Am Coll Cardiol 38(4):1231-65 (2001)

Fuster V and Ryden L E et al., “ACC/AHA/ESC Practice Guidelines—FullText,” J Am Coll Cardiol 38(4):1266i-1266lxx (2001)

Morady F et al., “Effects of resting vagal tone on accessoryatrioventricular connections,” Circulation 81(1):86-90 (1990)

Waninger M S et al., “Electrophysiological control of ventricular rateduring atrial fibrillation,” PACE 23:1239-1244 (2000)

Wijffels M C et al., “Electrical remodeling due to atrial fibrillationin chronically instrumented conscious goats: roles of neurohumoralchanges, ischemia, atrial stretch, and high rate of electricalactivation,” Circulation 96(10):3710-20 (1997)

Wijffels M C et al., “Atrial fibrillation begets atrial fibrillation,”Circulation 92:1954-1968 (1995)

Goldberger A L et al., “Vagally-mediated atrial fibrillation in dogs:conversion with bretylium tosylate,” Int J Cardiol 13(1):47-55 (1986)

Takei M et al., “Vagal stimulation prior to atrial rapid pacing protectsthe atrium from electrical remodeling in anesthetized dogs,” Jpn Circ J65(12):1077-81 (2001)

Friedrichs G S, “Experimental models of atrial fibrillation/flutter,” JPharmacological and Toxicological Methods 43:117-123 (2000)

Hayashi H et al., “Different effects of class Ic and III antiarrhythmicdrugs on vagotonic atrial fibrillation in the canine heart,” Journal ofCardiovascular Pharmacology 31:101-107 (1998)

Morillo C A et al., “Chronic rapid atrial pacing. Structural,functional, and electrophysiological characteristics of a new model ofsustained atrial fibrillation,” Circulation 91:1588-1595 (1995)

Lew S J et al., “Stroke prevention in elderly patients with atrialfibrillation,” Singapore Med J 43(4):198-201 (2002)

Higgins C B, “Parasympathetic control of the heart,” Pharmacol. Rev.25:120-155 (1973)

Hunt R, “Experiments on the relations of the inhibitory to theaccelerator nerves of the heart,” J. Exptl. Med. 2:151-179 (1897)

Billette J et al., “Roles of the AV junction in determining theventricular response to atrial fibrillation,” Can J Physiol Pharamacol53(4)575-85 (1975)

Stramba-Badiale M et al., “Sympathetic-Parasympathetic Interaction andAccentuated Antagonism in Conscious Dogs,” American Journal ofPhysiology 260 (2Pt 2):H335-340 (1991)

Garrigue S et al., “Post-ganglionic vagal stimulation of theatrioventricular node reduces ventricular rate during atrialfibrillation,” PACE 21(4), 878 (Part II) (1998)

Kwan H et al., “Cardiovascular adverse drug reactions during initiationof antiarrhythmic therapy for atrial fibrillation,” Can J Hosp Pharm54:10-14 (2001)

Jidéus L, “Atrial fibrillation after coronary artery bypass surgery: Astudy of causes and risk factors,” Acta Universitatis Upsaliensis,Uppsala, Sweden (2001)

Borovikova L V et al., “Vagus nerve stimulation attenuates the systemicinflammatory response to endotoxin,” Nature 405(6785):458-62 (2000)

Wang H et al., “Nicotinic acetylcholine receptor alpha-7 subunit is anessential regulator of inflammation,” Nature 421:384-388 (2003)

Vanoli E et al., “Vagal stimulation and prevention of sudden death inconscious dogs with a healed myocardial infarction,” Circ Res68(5):1471-81 (1991)

De Ferrari G M, “Vagal reflexes and survival during acute myocardialischemia in conscious dogs with healed myocardial infarction,” Am JPhysiol 261(1 Pt 2):H63-9 (1991)

Li D et al., “Promotion of Atrial Fibrillation by Heart Failure in Dogs:Atrial Remodeling of a Different Sort,” Circulation 100(1):87-95 (1999)

Feliciano L et al., “Vagal nerve stimulation during muscarinic andbeta-adrenergic blockade causes significant coronary artery dilation,”Cardiovasc Res 40(1):45-55 (1998)

A number of patents describe techniques for treating arrhythmias and/orischemia by, at least in part, stimulating the vagus nerve. Arrhythmiasin which the heart rate is too fast include fibrillation, flutter andtachycardia. Arrhythmia in which the heart rate is too slow is known asbradyarrhythmia. U.S. Pat. No. 5,700,282 to Zabara, which isincorporated herein by reference, describes techniques for stabilizingthe heart rhythm of a patient by detecting arrhythmias and thenelectronically stimulating the vagus and cardiac sympathetic nerves ofthe patient. The stimulation of vagus efferents directly causes theheart rate to slow down, while the stimulation of cardiac sympatheticnerve efferents causes the heart rate to quicken.

U.S. Pat. No. 5,330,507 to Schwartz, which is incorporated herein byreference, describes a cardiac pacemaker for preventing or interruptingtachyarrhythmias and for applying pacing therapies to maintain the heartrhythm of a patient within acceptable limits. The device automaticallystimulates the right or left vagus nerves as well as the cardiac tissuein a concerted fashion dependent upon need. Continuous and/or phasicelectrical pulses are applied. Phasic pulses are applied in a specificrelationship with the R-wave of the ECG of the patient.

European Patent Application EP 0 688 577 to Holmström et al., which isincorporated herein by reference, describes a device to treat atrialtachyarrhythmia by detecting arrhythmia and stimulating aparasympathetic nerve that innervates the heart, such as the vagusnerve.

U.S. Pat. Nos. 5,690,681 and 5,916,239 to Geddes et al., which areincorporated herein by reference, describe closed-loop,variable-frequency, vagal-stimulation apparatus for control ofventricular rate during atrial fibrillation. The apparatus stimulatesthe left vagus nerve, and automatically and continuously adjusts thevagal stimulation frequency as a function of the difference betweenactual and desired ventricular excitation rates. In an alternativeembodiment, the apparatus automatically adjusts the vagal stimulationfrequency as a function of the difference between ventricular excitationrate and arterial pulse rate in order to eliminate or minimize pulsedeficit.

US Patent Publication 2003/0229380 to Adams et al., which isincorporated herein by reference, describes techniques for electricallystimulating the right vagus nerve in order to reduce the heart rate of apatient suffering from conditions such as chronic heart failure,ischemia, or acute myocardial infarction. The amount of energy of thestimulation may be determined in accordance with a difference betweenthe patient's actual heart rate and a maximum target heart rate for thepatient. Delivery of energy is preferably synchronized with thedetection of a P-wave. Automatic adjustment of the target heart rate maybe based on current day and/or time of day information, and patientphysical activity. The voltage, pulse width, or number of pulses in thestimulation may be controlled.

U.S. Pat. No. 5,203,326 to Collins, which is incorporated herein byreference, describes a pacemaker which detects a cardiac abnormality andresponds with electrical stimulation of the heart combined with vagusnerve stimulation. The vagal stimulation frequency is progressivelyincreased in one-minute intervals, and, for the pulse delivery rateselected, the heart rate is described as being slowed to a desired,stable level by increasing the pulse current.

U.S. Pat. No. 6,511,500 to Rahme, which is incorporated herein byreference, describes various aspects of the effects of autonomic nervoussystem tone on atrial arrhythmias, and its interaction with class IIIantiarrhythmic drug effects. The significance of sympathetic andparasympathetic activation are described as being evaluated bydetermining the effects of autonomic nervous system using vagal andstellar ganglions stimulation, and by using autonomic nervous systemneurotransmitters infusion (norepinephrine, acetylcholine).

U.S. Pat. No. 5,199,428 to Obel et al., which is incorporated herein byreference, describes a cardiac pacemaker for detecting and treatingmyocardial ischemia. The device automatically stimulates the vagalnervous system as well as the cardiac tissue in a concerted fashion inorder to decrease cardiac workload and thereby protect the myocardium.

U.S. Pat. Nos. 5,334,221 to Bardy and 5,356,425 to Bardy et al., whichare incorporated herein by reference, describe a stimulator for applyingstimulus pulses to the AV nodal fat pad in response to the heart rateexceeding a predetermined rate, in order to reduce the ventricular rate.The device also includes a cardiac pacemaker which serves to pace theventricle in the event that the ventricular rate is lowered below apacing rate, and provides for feedback control of the stimulusparameters applied to the AV nodal fat pad, as a function of thedetermined effect of the stimulus pulses on the heart rate.

U.S. Pat. No. 5,522,854 to Ideker et al., which is incorporated hereinby reference, describes techniques for preventing arrhythmia bydetecting a high risk of arrhythmia and then stimulating afferent nervesto prevent the arrhythmia.

U.S. Pat. No. 6,434,424 to Igel et al., which is incorporated herein byreference, describes a pacing system with a mode switching feature andventricular rate regularization function adapted to stabilize orregularize ventricular heart rate during chronic or paroxysmal atrialtachyarrhythmia.

US Patent Application Publication 2002/0120304 to Mest, which isincorporated herein by reference, describes a method for regulating theheart rate of a patient by inserting into a blood vessel of the patienta catheter having an electrode at its distal end, and directing thecatheter to an intravascular location so that the electrode is adjacentto a selected cardiac sympathetic or parasympathetic nerve.

U.S. Pat. Nos. 6,006,134 and 6,266,564 to Hill et al., which areincorporated herein by reference, describe an electro-stimulation deviceincluding a pair of electrodes for connection to at least one locationin the body that affects or regulates the heartbeat.

PCT Publication WO 02/085448 to Foreman et al., which is incorporatedherein by reference, describes a method for protecting cardiac functionand reducing the impact of ischemia on the heart, by electricallystimulating a neural structure capable of carrying the predeterminedelectrical signal from the neural structure to the “intrinsic cardiacnervous system,” which is defined and described therein.

U.S. Pat. No. 5,243,980 to Mehra, which is incorporated herein byreference, describes techniques for discrimination between ventricularand supraventricular tachycardia. In response to the detection of theoccurrence of a tachycardia, stimulus pulses are delivered to one orboth of the SA and AV nodal fat pads. The response of the heart rhythmto these stimulus pulses is monitored. Depending upon the change or lackof change in the heart rhythm, a diagnosis is made as to the origin ofthe tachycardia.

U.S. Pat. No. 5,658,318 to Stroetmann et al., which is incorporatedherein by reference, describes a device for detecting a state ofimminent cardiac arrhythmia in response to activity in nerve signalsconveying information from the autonomic nerve system to the heart. Thedevice comprises a sensor adapted to be placed in an extracardiacposition and to detect activity in at least one of the sympathetic andvagus nerves.

U.S. Pat. No. 6,292,695 to Webster, Jr. et al., which is incorporatedherein by reference, describes a method for controlling cardiacfibrillation, tachycardia, or cardiac arrhythmia by the use of acatheter comprising a stimulating electrode, which is placed at anintravascular location. The electrode is connected to a stimulatingmeans, and stimulation is applied across the wall of the vessel,transvascularly, to a sympathetic or parasympathetic nerve thatinnervates the heart at a strength sufficient to depolarize the nerveand effect the control of the heart.

U.S. Pat. No. 6,134,470 to Hartlaub, which is incorporated herein byreference, describes an implantable anti-arrhythmia system whichincludes a spinal cord stimulator coupled to an implantable heart rhythmmonitor. The monitor is adapted to detect the occurrence oftachyarrhythmias or of precursors thereto and, in response, trigger theoperation of the spinal cord stimulator in order to prevent occurrencesof tachyarrhythmias and/or as a stand-alone therapy for termination oftachyarrhythmias and/or to reduce the level of aggressiveness requiredof an additional therapy such as antitachycardia pacing, cardioversionor defibrillation.

A number of patents and articles describe other methods and devices forstimulating nerves to achieve a desired effect. Often these techniquesinclude a design for an electrode or electrode cuff.

US Patent Publication 2003/0050677 to Gross et al., which is assigned tothe assignee of the present patent application and is incorporatedherein by reference, describes apparatus for applying current to anerve. A cathode is adapted to be placed in a vicinity of a cathodiclongitudinal site of the nerve and to apply a cathodic current to thenerve. A primary inhibiting anode is adapted to be placed in a vicinityof a primary anodal longitudinal site of the nerve and to apply aprimary anodal current to the nerve. A secondary inhibiting anode isadapted to be placed in a vicinity of a secondary anodal longitudinalsite of the nerve and to apply a secondary anodal current to the nerve,the secondary anodal longitudinal site being closer to the primaryanodal longitudinal site than to the cathodic longitudinal site.

U.S. Pat. Nos. 4,608,985 to Crish et al. and 4,649,936 to Ungar et al.,which are incorporated herein by reference, describe electrode cuffs forselectively blocking orthodromic action potentials passing along a nervetrunk, in a manner intended to avoid causing nerve damage.

PCT Patent Publication WO 01/10375 to Felsen et al., which isincorporated herein by reference, describes apparatus for modifying theelectrical behavior of nervous tissue. Electrical energy is applied withan electrode to a nerve in order to selectively inhibit propagation ofan action potential.

U.S. Pat. No. 5,755,750 to Petruska et al., which is incorporated hereinby reference, describes techniques for selectively blocking differentsize fibers of a nerve by applying direct electric current between ananode and a cathode that is larger than the anode. The current appliedto the electrodes blocks nerve transmission, but, as described, does notactivate the nerve fibers in either direction.

The following articles, which are incorporated herein by reference, maybe of interest:

Ungar I J et al., “Generation of unidirectionally propagating actionpotentials using a monopolar electrode cuff,” Annals of BiomedicalEngineering, 14:437-450 (1986)

Sweeney J D et al., “An asymmetric two electrode cuff for generation ofunidirectionally propagated action potentials,” IEEE Transactions onBiomedical Engineering, vol. BME-33(6) (1986)

Sweeney J D et al., “A nerve cuff technique for selective excitation ofperipheral nerve trunk regions,” IEEE Transactions on BiomedicalEngineering, 37(7) (1990)

Naples G G et al., “A spiral nerve cuff electrode for peripheral nervestimulation,” by IEEE Transactions on Biomedical Engineering, 35(11)(1988)

van den Honert C et al., “Generation of unidirectionally propagatedaction potentials in a peripheral nerve by brief stimuli,” Science,206:1311-1312 (1979)

van den Honert C et al., “A technique for collision block of peripheralnerve: Single stimulus analysis,” MP-11, IEEE Trans. Biomed. Eng.28:373-378 (1981)

van den Honert C et al., “A technique for collision block of peripheralnerve: Frequency dependence,” MP-12, IEEE Trans. Biomed. Eng. 28:379-382(1981)

Rijkhoff N J et al., “Acute animal studies on the use of anodal block toreduce urethral resistance in sacral root stimulation,” IEEETransactions on Rehabilitation Engineering, 2(2):92 (1994)

Mushahwar V K et al., “Muscle recruitment through electrical stimulationof the lumbo-sacral spinal cord,” IEEE Trans Rehabil Eng, 8(1):22-9(2000)

Deurloo K E et al., “Transverse tripolar stimulation of peripheralnerve: a modelling study of spatial selectivity,” Med Biol Eng Comput,36(1):66-74 (1998)

Tarver W B et al., “Clinical experience with a helical bipolarstimulating lead,” Pace, Vol. 15, October, Part II (1992)

Manfredi M, “Differential block of conduction of larger fibers inperipheral nerve by direct current,” Arch. Ital. Biol., 108:52-71 (1970)

In physiological muscle contraction, nerve fibers are recruited in theorder of increasing size, from smaller-diameter fibers to progressivelylarger-diameter fibers. In contrast, artificial electrical stimulationof nerves using standard techniques recruits fibers in a larger- tosmaller-diameter order, because larger-diameter fibers have a lowerexcitation threshold. This unnatural recruitment order causes musclefatigue and poor force gradation. Techniques have been explored to mimicthe natural order of recruitment when performing artificial stimulationof nerves to stimulate muscles.

Fitzpatrick et al., in “A nerve cuff design for the selective activationand blocking of myelinated nerve fibers,” Ann. Conf. of the IEEE Eng. inMedicine and Biology Soc, 13(2), 906 (1991), which is incorporatedherein by reference, describe a tripolar electrode used for musclecontrol. The electrode includes a central cathode flanked on itsopposite sides by two anodes. The central cathode generates actionpotentials in the motor nerve fiber by cathodic stimulation. One of theanodes produces a complete anodal block in one direction so that theaction potential produced by the cathode is unidirectional. The otheranode produces a selective anodal block to permit passage of the actionpotential in the opposite direction through selected motor nerve fibersto produce the desired muscle stimulation or suppression.

The following articles, which are incorporated herein by reference, maybe of interest:

Rijkhoff N J et al., “Orderly recruitment of motoneurons in an acuterabbit model,” Ann. Conf. of the IEEE Eng., Medicine and Biology Soc.,20(5):2564 (1998)

Rijkhoff N J et al., “Selective stimulation of small diameter nervefibers in a mixed bundle,” Proceedings of the Annual Project MeetingSensations/Neuros and Mid-Term Review Meeting on the TMR-Network Neuros,Apr. 21-23, 1999, pp. 20-21 (1999)

Baratta R et al., “Orderly stimulation of skeletal muscle motor unitswith tripolar nerve cuff electrode,” IEEE Transactions on BiomedicalEngineering, 36(8):836-43 (1989)

The following articles, which are incorporated herein by reference,describe techniques using point electrodes to selectively exciteperipheral nerve fibers:

Grill W M et al., “Inversion of the current-distance relationship bytransient depolarization,” IEEE Trans Biomed Eng, 44(1):1-9 (1997)

Goodall E V et al., “Position-selective activation of peripheral nervefibers with a cuff electrode,” IEEE Trans Biomed Eng, 43(8):851-6 (1996)

Veraart C et al., “Selective control of muscle activation with amultipolar nerve cuff electrode,” IEEE Trans Biomed Eng, 40(7):640-53(1993)

As defined by Rattay, in the article, “Analysis of models forextracellular fiber stimulation,” IEEE Transactions on BiomedicalEngineering, Vol. 36, no. 2, p. 676, 1989, which is incorporated hereinby reference, the activation function is the second spatial derivativeof the electric potential along an axon. In the region where theactivation function is positive, the axon depolarizes, and in the regionwhere the activation function is negative, the axon hyperpolarizes. Ifthe activation function is sufficiently positive, then thedepolarization will cause the axon to generate an action potential;similarly, if the activation function is sufficiently negative, thenlocal blocking of action potentials transmission occurs. The activationfunction depends on the current applied, as well as the geometry of theelectrodes and of the axon.

For a given electrode geometry, the equation governing the electricalpotential is:∇(σ∇U)=4πj,

where U is the potential, σ is the conductance tensor specifying theconductance of the various materials (electrode housing, axon,intracellular fluid, etc.), and j is a scalar function representing thecurrent source density specifying the locations of current injection.

U.S. Pat. No. 5,231,988 to Wernicke et al., which is incorporated hereinby reference, describes techniques for treating and controlling diabetesand other systemic pancreatic endocrine disorders attributable toabnormal levels of secretion of endogenous insulin. An electricalstimulator implanted into or worn external to the patient's body isadapted, when activated, to generate a programmable electrical waveformfor application to electrodes implanted on the vagus nerve of thepatient. The electrical waveform is programmed using parameter valuesselected to stimulate or inhibit the vagus nerve to modulate theelectrical activity thereof to increase or decrease secretion of naturalinsulin by the patient's pancreas. The stimulator is selectivelyactivated manually by the patient in response to direct measurement ofblood glucose or symptoms, or is activated automatically by programmingthe activation to occur at predetermined times and for predeterminedintervals during the circadian cycle of the patient. Alternatively, theautomatic activation is achieved using an implanted sensor to detect theblood glucose concentration, and is triggered when the patient's bloodglucose concentration exceeds or falls below a predetermined leveldepending on whether diabetes or hypoglycemia is being treated.

SUMMARY OF THE INVENTION

In some embodiments of the present invention, a method for enhancing orsustaining the efficacy of drug treatment for atrial fibrillation (AF)comprises administering a drug to a patient and applying signals to avagus nerve that innervates the heart of the patient. The drugadministered typically includes a sinus rhythm maintenance drug (i.e.,an antiarrhythmic drug) or a ventricular rate control drug. The efficacyof the drug is typically enhanced or sustained by (a) configuring thesignals so as to prevent electrical remodeling of the atria, whichremodeling generally reduces drug effectiveness over time, and/or (b)configuring the signals so as to achieve a therapeutic benefit similarto that of the drug, which typically results in a synergistic effectbetween the therapeutic benefit of the drug and the vagal stimulation.For enhancing the effectiveness of antiarrhythmic drugs, the signals aretypically configured to increase vagal tone, produce rhythmic vagalactivity, and/or reduce the atrial effective refractory period (AERP).The effectiveness of ventricular rate control drugs is typicallyenhanced by applying vagal stimulation to control ventricular responserate and/or to improve cardiac output.

In some embodiments of the present invention, a method for enhancing orsustaining the efficacy of drug treatment for AF comprises administeringa drug to the patient, applying signals to the vagus nerve, andconfiguring the signals to reduce the mechanical tension on at least oneatrium of the subject. Such reduced mechanical tension generally reducesthe risk of AF. For some applications, such vagal stimulation is appliedwithout administering the drug.

In some embodiments of the present invention, the safety of a drugadministered to the patient is improved by applying signals to the vagusnerve, and configuring the signals so as to prevent adverse effectssometimes caused by the drug, such as repolarization abnormalities(e.g., prolongation of the QT interval), bradycardia, and/or ventriculartachyarrhythmia (e.g., ventricular fibrillation). In some cases, thedrug can safely be administered to patients who otherwise could nottolerate the drug because of such adverse effects. In addition, in somecases, adverse effects of the drug are prevented or diminished byallowing the use of lower dosages of the drug by enhancing or sustainingthe efficacy of the drug, as described above.

In some embodiments of the present invention, a method for enhancing orsustaining the efficacy of drug treatment for heart failure comprisesadministering a drug to a patient and applying signals to a vagus nervethat innervates the heart of the patient. The signals are configured soas to treat the heart failure, which typically results in a synergisticeffect between the therapeutic benefit of the drug and the vagalstimulation. Alternatively or additionally, the signals are configuredso as to prevent adverse effects sometimes caused by the drug, such asventricular arrhythmia, idioventricular arrhythmia, prematureventricular contractions, and/or ventricular tachycardia. In addition,in some cases, adverse effects of the drug are prevented or diminishedby allowing the use of lower dosages of the drug because of thesynergistic effect of the vagal stimulation with the drug treatment.

In some embodiments of the present invention, a method for increasingvagal tone comprises applying signals to the vagus nerve, andconfiguring the signals to stimulate the vagus nerve, thereby deliveringparasympathetic nerve stimulation to the heart, while at the same timeminimizing the heart-rate-lowering effects of the stimulation. Suchtreatment generally results in the beneficial effects of vagalstimulation in clinical situations in which heart rate reduction is notindicated or is contraindicated. For example, such treatment istypically appropriate for heart failure patients who suffer frombradycardia when taking beta-blockers. In addition, such treatment isbelieved by the inventors to reduce the risk of sudden cardiac death insome patients.

In some embodiments of the present invention, a method for preventing orreducing fibrosis and/or inflammation of the heart comprises applyingsignals to a vagus nerve that innervates the heart of the patient.Substantially continuous application of such stimulation generallymodulates immune system responses, thereby reducing atrial, ventricular,and/or coronary inflammation and/or fibrosis. For some applications,such stimulation is applied for more than about three weeks. Conditionsthat are believed to be at least partially immune-modulated, andtherefore to generally benefit from such vagal stimulation, include, butare not limited to, atrial and ventricular remodeling (e.g., induced byAF, heart failure, myocarditis, and/or myocardial infarct), restenosis,and atherosclerosis.

In some embodiments of the present invention, signals are applied to avagus nerve of a patient, and the signals are configured to inhibitpropagation of naturally-generated efferent action potentials in thevagus nerve. It is hypothesized by the inventors that such inhibition isuseful for treating AF, typically by enhancing drug efficacy, and forpreventing bradycardia.

In some embodiments of the present invention, electrical signals areapplied, typically on a long-term basis, to a vagus nerve of a subjectnot necessarily suffering from a heart condition, in order to increasethe life expectancy, quality of life, and/or healthiness of the subject.Such signals are typically configured to not reduce the heart rate belownormal range for a typical human. Such chronic vagal stimulation ishypothesized by the inventors to be effective for increasing lifeexpectancy, quality of life, and/or healthiness by (a) causing areduction in or prevention of cardiovascular disease and/or events, (b)having an anti-inflammatory effect in the heart or in the rest of thebody, (c) reducing the average heart rate, (d) reducing metabolic rate,and/or (e) generally having an anti-stress effect.

In some embodiments of the present invention, apparatus is provided forapplying the signals to the vagus nerve, comprising an electrode deviceand a control unit. The electrode device is applied to a portion of thevagus nerve that innervates the heart of the patient. The control unitdrives the electrode device to apply signals to the vagus nerve, andconfigures the signals based on the desired therapeutic effect, asdescribed above.

In some embodiments of the present invention, when applying the signalsto the vagus nerve, the control unit drives the electrode device to (a)apply signals to induce the propagation of efferent action potentialstowards the heart, and (b) suppress artificially-induced afferent actionpotentials towards the brain, in order to minimize any unintended sideeffect of the signal application. When inducing efferent actionpotentials towards the heart, the control unit typically drives theelectrode device to selectively recruit nerve fibers beginning withsmaller-diameter fibers, and to recruit progressively larger-diameterfibers as the desired stimulation level increases. Typically, in orderto achieve this smaller-to-larger diameter fiber recruitment order, thecontrol unit stimulates fibers essentially of all diameters usingcathodic current from a central cathode, while simultaneously inhibitingfibers in a larger-to-smaller diameter order using anodal current(“efferent anodal current”) from a set of one or more anodes placedbetween the central cathode and the edge of the electrode device closerto the heart (“the efferent anode set”). Thus, for example, if a smallanodal current is applied, then action potentials induced by thecathodic current in the larger diameter fibers are inhibited (becausethe larger diameter fibers are sensitive to even a small anodalcurrent), while action potentials induced by the cathodic current insmaller fibers are allowed to propagate towards the heart. The amount ofparasympathetic stimulation delivered to the heart may generally beincreased by decreasing the number of fibers affected by the efferentanodal current, in a smaller-to-larger diameter order, e.g., bydecreasing the amplitude or frequency of the efferent anodal currentapplied to the nerve. Alternatively, the cathodic current is increasedin order to increase the parasympathetic stimulation.

The control unit typically suppresses afferent action potentials inducedby the cathodic current by inhibiting essentially all or a largefraction of fibers using anodal current (“afferent anodal current”) froma second set of one or more anodes (the “afferent anode set”). Theafferent anode set is typically placed between the central cathode andthe edge of the electrode device closer to the brain (the “afferentedge”), to block a large fraction of fibers from conveying signals inthe direction of the brain during application of the afferent anodalcurrent.

In some embodiments of the present invention, the cathodic current isapplied with an amplitude sufficient to induce action potentials inlarge- and medium-diameter fibers (e.g., A- and B-fibers), butinsufficient to induce action potentials in small-diameter fibers (e.g.,C-fibers). Simultaneously, an anodal current is applied in order toinhibit action potentials induced by the cathodic current in thelarge-diameter fibers (e.g., A-fibers). This combination of cathodic andanodal current generally results in the stimulation of medium-diameterfibers (e.g., B-fibers) only. At the same time, a portion of theafferent action potentials induced by the cathodic current are blocked,as described above. By not stimulating large-diameter fibers, suchstimulation generally avoids adverse effects sometimes associated withrecruitment of such large fibers, such as dyspnea and hoarseness.Stimulation of small-diameter fibers is avoided because these fiberstransmit pain sensations and are important for regulation of reflexessuch as respiratory reflexes.

In some embodiments of the present invention, the efferent anode setcomprises a plurality of anodes. Application of the efferent anodalcurrent in appropriate ratios from the plurality of anodes in theseembodiments generally minimizes the “virtual cathode effect,” wherebyapplication of too large an anodal current creates a virtual cathode,which stimulates rather than blocks fibers. When such techniques are notused, the virtual cathode effect generally hinders blocking ofsmaller-diameter fibers, because a relatively large anodal current istypically necessary to block such fibers, and this same large anodalcurrent induces the virtual cathode effect. Likewise, the afferent anodeset typically comprises a plurality of anodes in order to minimize thevirtual cathode effect in the direction of the brain.

In some embodiments of the present invention, vagal stimulation isapplied in a series of pulses. The application of the series of pulsesin each cardiac cycle typically commences after a variable delay after adetected R-wave, P-wave, or other feature of an ECG. For someapplications, other parameters of the applied series of pulses are alsovaried in real time. Such other parameters include amplitude, number ofpulses per trigger (PPT), pulse duration, and pulse repetition interval(i.e., the interval between the leading edges of two consecutivepulses). For some applications, the delay and/or one or more of theother parameters are calculated in real time using a function, theinputs of which include one or more pre-programmed but updateableconstants and one or more sensed parameters, such as the R-R intervalbetween cardiac cycles and/or the P-R interval. Alternatively oradditionally, a lookup table of parameters, such as delays and/or otherparameters, is used to determine in real time the appropriate parametersfor each application of pulses, based on the one or more sensedparameters, and/or based on a predetermined sequence stored in thelookup table.

“Vagus nerve,” and derivatives thereof, as used in the specification andthe claims, is to be understood to include portions of the left vagusnerve, the right vagus nerve, and branches of the vagus nerve such asthe superior cardiac nerve, superior cardiac branch, and inferiorcardiac branch. Similarly, stimulation of the vagus nerve is describedherein by way of illustration and not limitation, and it is to beunderstood that stimulation of other autonomic nerves, including nervesin the epicardial fat pads, a carotid artery, an internal jugular vein,a carotid sinus, a vena cava vein, and/or a pulmonary vein, fortreatment of heart conditions or other conditions, is also includedwithin the scope of the present invention.

There is therefore provided, in accordance with an embodiment of thepresent invention, a method for treating a subject suffering from atrialfibrillation (AF), including:

administering a drug for treating the AF to the subject;

applying a current to a site of the subject selected from the listconsisting of: a vagus nerve of the subject, an epicardial fat pad ofthe subject, a pulmonary vein of the subject, a carotid artery of thesubject, a carotid sinus of the subject, a vena cava vein of thesubject, and an internal jugular vein of the subject; and

configuring the current to increase vagal tone of the subject, so as totreat the AF.

In an embodiment, configuring the current includes configuring thecurrent so as to enhance an efficacy of the drug.

In an embodiment, the method includes detecting an occurrence of the AF,and applying the current includes applying the current responsive to thedetecting of the occurrence.

In an embodiment, administering the drug includes administering the drugat a dosage determined independently of applying the current.

In an embodiment, administering the drug includes administering the drugat a dosage lower than a dosage determined independently of applying thecurrent.

In an embodiment, the subject additionally suffers from heart failure(HF), and the method includes administering a HF drug for treating theHF of the subject, and configuring the current includes configuring thecurrent so as to enhance an efficacy of the HF drug.

For some applications, configuring the current so as to enhance theefficacy of the drug includes configuring the current so as to preventelectrical remodeling of at least one atrium of the subject.Alternatively or additionally, configuring the current so as to enhancethe efficacy of the drug includes configuring the current so as to delayelectrical remodeling of at least one atrium of the subject.

In an embodiment, configuring the current so as to enhance the efficacyof the drug includes configuring the current so as to achieve atherapeutic effect similar to that of the drug.

In an embodiment, configuring the current so as to enhance the efficacyof the drug includes configuring the current so as to reduce a QTinterval of an electrocardiogram (ECG) of the subject.

In an embodiment, administering the drug includes administering abeta-blocker.

In an embodiment, administering the drug includes administering a sinusrhythm maintenance drug. For some applications, configuring the currentso as to enhance the efficacy of the drug includes configuring thecurrent so as to increase vagal tone of the subject. For someapplications, configuring the current so as to enhance the efficacy ofthe drug includes configuring the current so as to reduce an atrialeffective refractory period of the subject. For some applications,configuring the current so as to enhance the efficacy of the drugincludes configuring the current so as to have an antiarrhythmic effecton an atrium of the subject. For some applications, configuring thecurrent so as to enhance the efficacy of the drug includes configuringthe current to reduce mechanical tension on at least one atrium of thesubject.

For some applications, administering the sinus rhythm maintenance drugincludes administering a beta-blocker. Alternatively or additionally,administering the sinus rhythm maintenance drug includes administeringquinidine. Further alternatively or additionally, administering thesinus rhythm maintenance drug includes administering a drug selectedfrom the list consisting of: digoxin, amiodarone, disopyramide,dofetilide, a class IC drug, procainamide, and sotalol.

For some applications, the method includes applying conventionalcardioversion to the subject so as to treat the AF. For someapplications, configuring the current so as to enhance the efficacy ofthe drug includes configuring the current so as to induce rhythmic vagalactivity in the subject.

In an embodiment, administering the drug includes administering aventricular rate control drug. For some applications, configuring thecurrent so as to enhance the efficacy of the drug includes configuringthe current so as to control a ventricular response rate of the subject.For some applications, configuring the current so as to enhance theefficacy of the drug includes configuring the current so as to improvecardiac output of the subject.

For some applications, administering the ventricular rate control drugincludes administering a beta-blocker. Alternatively or additionally,administering the ventricular rate control drug includes administering adrug selected from the list consisting of: a calcium channel antagonistand digoxin.

In an embodiment, administering the drug includes administering anantithrombotic drug. For some applications, administering theantithrombotic drug includes administering an anticoagulation drug thatinhibits a coagulation cascade. Alternatively or additionally,administering the antithrombotic drug includes administering a drug thatinhibits platelet aggregation. For some applications, configuring thecurrent so as to enhance the efficacy of the antithrombotic drugincludes configuring the current so as to increase atrial motion of thesubject. For some applications, administering the antithrombotic drugincludes selecting a dosage of the drug to achieve a targetinternational normalized ratio (INR) lower than a target INR determinedindependently of applying the current. For some applications,configuring the current so as to enhance the efficacy of the drugincludes configuring the current so as to induce rhythmic vagal activityin the subject.

There is also provided, in accordance with an embodiment of the presentinvention, a method for treating a subject suffering from heart failure(HF), including:

administering a drug for treating the HF to the subject;

applying a current to a site of the subject selected from the listconsisting of: a vagus nerve of the subject, an epicardial fat pad ofthe subject, a pulmonary vein of the subject, a carotid artery of thesubject, a carotid sinus of the subject, a vena cava vein of thesubject, and an internal jugular vein of the subject; and

configuring the current so as to enhance an efficacy of the drug.

In an embodiment, configuring the current so as to enhance the efficacyof the drug includes configuring the current so as to treat the HF.

For some applications, configuring the current so as to enhance theefficacy of the drug includes configuring the current to inhibitpropagation of naturally-generated efferent action potentials travelingthrough the site.

In an embodiment, administering the drug includes administering apositive inotropic drug. For some applications, administering thepositive inotropic drug includes administering a positive inotropic drugselected from the list consisting of: digoxin, dopamine, dobutamine,adrenaline, amrinone, and milrinone.

In an embodiment, administering the drug includes administering apreload reduction drug. For some applications, administering the preloadreduction drug includes administering a preload reduction drug selectedfrom the list consisting of: an ACE inhibitor, a nitrate, and sodiumnitroprusside. For some applications, configuring the current so as toenhance the efficacy of the preload reduction drug includes configuringthe current so as to decrease atrial contractile force of a heart of thesubject. For some applications, applying the current includes applyingthe current to the site intermittently during alternating “on” and “off”periods. For some applications, applying the current intermittentlyincludes setting each of the “on” periods to have a duration of betweenabout 1 and about 15 seconds, and each of the “off” periods to have aduration of between about 5 and about 20 seconds.

There is further provided, in accordance with an embodiment of thepresent invention, a method for treating a subject suffering from acondition, including:

applying a current to a site of the subject selected from the listconsisting of: a vagus nerve of the subject, an epicardial fat pad ofthe subject, a pulmonary vein of the subject, a carotid artery of thesubject, a carotid sinus of the subject, a vena cava vein of thesubject, and an internal jugular vein of the subject; and

configuring the current to increase vagal tone of the subject, and tominimize an effect of the applying of the current on a heart rate of thesubject, so as to treat the condition.

In an embodiment, the condition is selected from the list consisting of:atrial fibrillation, heart failure, atherosclerosis, restenosis,myocarditis, cardiomyopathy, post-myocardial infarct remodeling, andhypertension, and configuring the current includes configuring thecurrent so as to treat the selected condition. Alternatively oradditionally, the condition is selected from the list consisting of:obesity, constipation, irritable bowl syndrome, rheumatoid arthritis,glomerulonephritis, an autoimmune disease, multiple sclerosis,hepatitis, pancreatitis, portal vein hypertension, thyroiditis, type Idiabetes, and type II diabetes, and configuring the current includesconfiguring the current so as to treat the selected condition.

For some applications, configuring the current includes configuring thecurrent so as to reduce a risk of sudden cardiac death of the subject.

For some applications, applying the current includes applying thecurrent substantially only at nighttime. For some applications, applyingthe current includes applying the current during a daytime period andduring a nighttime period, the applying during the nighttime periodbeing longer than the applying during the daytime period.

For some applications, applying the current includes detecting exerciseby the subject, and applying the current responsively to the detecting.

For some applications, applying the current to the site of the subjectincludes selecting a subject that is receiving a heart-rate loweringdrug, and who has achieved a heart rate within a desired range prior toinitiation of applying the current.

For some applications, applying the current to the site of the subjectincludes selecting a subject who experiences, when the heart rate isreduced, a symptom selected from the list consisting of: discomfort, anda reduction in exercise capacity.

For some applications, applying the current to the site of the subjectincludes selecting a subject who has a tendency towards bradycardia whenreceiving vagal stimulation that is not configured to minimize an effectthereof on the heart rate.

For some applications, the condition includes low cardiac output, andconfiguring the current includes configuring the current so as to treatthe low cardiac output. For some applications, the condition includesacute myocardial infarction with cardiogenic shock, and configuring thecurrent includes configuring the current so as to treat the acutemyocardial infarction. For some applications, the condition includesheart failure and beta-blocker-induced bradycardia, and configuring thecurrent includes configuring the current so as to treat the heartfailure and bradycardia.

In an embodiment, the method includes applying a pacing signal to aheart of the subject in conjunction with applying the current to thesite.

In an embodiment, the method includes sensing a heart rate of thesubject, and configuring the current includes configuring the currentusing a feedback loop, an input of which is the sensed heart rate.

There is still further provided, in accordance with an embodiment of thepresent invention, a method for treating a subject suffering from acondition, including:

administering to the subject a drug for treating the condition;

applying a current to a site of the subject selected from the listconsisting of: a vagus nerve of the subject, an epicardial fat pad ofthe subject, a pulmonary vein of the subject, a carotid artery of thesubject, a carotid sinus of the subject, a vena cava vein of thesubject, and an internal jugular vein of the subject; and

configuring the current so as to reduce an adverse effect sometimescaused by the drug.

In an embodiment, the condition includes atrial fibrillation (AF),administering the drug includes administering a drug for treating theAF, and configuring the current includes configuring the current so asto reduce the adverse effect sometimes caused by the AF drug.

In an embodiment, the condition includes heart failure (HF),administering the drug includes administering a drug for treating theHF, and configuring the current includes configuring the current so asto reduce the adverse effect sometimes caused by the HF drug.

In an embodiment, the condition includes an emergency condition, andadministering the drug includes administering atropine.

In an embodiment, the adverse effect includes idioventriculararrhythmia, and configuring the current includes configuring the currentso as to reduce the idioventricular arrhythmia. In an embodiment, theadverse effect includes premature ventricular contractions, andconfiguring the current includes configuring the current so as to reducethe premature ventricular contractions. In an embodiment, the adverseeffect includes ventricular tachycardia, and configuring the currentincludes configuring the current so as to reduce the ventriculartachycardia.

In an embodiment, the adverse effect includes ventricular arrhythmia,and configuring the current includes configuring the current so as toreduce the ventricular arrhythmia. For some applications, configuringthe current includes configuring the current so as to induce rhythmicvagal activity in the subject.

In an embodiment, administering the drug includes administering the drugat a dosage lower than a usual dosage determined independently ofapplying the current, and configuring the current includes configuringthe current so as to enhance an efficacy of the drug to a degree thatthe lower dosage has substantially the same efficacy as the usualdosage. For some applications, administering the drug includesadministering digoxin at the lower dosage.

In an embodiment, the adverse effect includes ventriculartachyarrhythmia, and configuring the current includes configuring thecurrent so as to reduce the ventricular tachyarrhythmia. For someapplications, the ventricular tachyarrhythmia includes ventricularfibrillation, and configuring the current includes configuring thecurrent so as to reduce the ventricular fibrillation. For someapplications, administering the drug includes administering a drugselected from the list consisting of: an antiarrhythmic drug, and apositive inotropic drug.

In an embodiment, the adverse effect includes a repolarizationabnormality, and configuring the current includes configuring thecurrent so as to reduce the repolarization abnormality. For someapplications, the repolarization abnormality includes a prolongation ofa QT interval of the subject, and configuring the current includesconfiguring the current so as to reduce the prolongation of the QTinterval.

In an embodiment, administering the drug includes administering the drugat a dosage greater than a dosage determined independently of applyingthe current, and configuring the current so as to reduce the adverseeffect includes configuring the current so as to reduce an adverseeffect sometimes caused by the greater dosage. For some applications,administering the drug includes administering a class IC drug.

In an embodiment, administering the drug includes administering apositive inotropic agent for a period of time having a duration greaterthan about one day. For some applications, administering the positiveinotropic agent includes administering the positive inotropic agent fora period having a duration greater than about 7 days. For someapplications, administering the positive inotropic agent includesadministering a positive inotropic agent other than digitalis. For someapplications, the adverse effect is selected from the list consistingof: a chronotropic effect of the positive inotropic agent, and aproarrhythmic effect of the positive inotropic agent, and configuringthe current includes configuring the current so as to reduce theselected adverse effect. For some applications, the subject is in astable condition, and administering the positive inotropic agentincludes administering the positive inotropic agent to the stablesubject.

In an embodiment, the adverse effect includes an occurrence ofbradycardia, and configuring the current includes configuring thecurrent so as to reduce the occurrence of bradycardia. For someapplications, configuring the current includes configuring the currentto inhibit propagation of naturally-generated efferent action potentialstraveling through the site, so as to reduce the bradycardia. For someapplications, applying the current includes detecting the occurrence ofbradycardia, and terminating applying the current responsive to thedetecting. For some applications, applying the current includesdetecting the occurrence of bradycardia, and reducing an intensity ofthe current responsive to the detecting. For some applications, themethod includes detecting the occurrence of bradycardia, and, responsiveto the detecting, applying a pacing signal to a heart of the subject.

There is additionally provided, in accordance with an embodiment of thepresent invention, a method for treating a subject, including:

applying a current to a site of the subject selected from the listconsisting of: a vagus nerve of the subject, and epicardial fat pad ofthe subject, a pulmonary vein of the subject, a carotid artery of thesubject, a carotid sinus of the subject, a vena cava vein of thesubject, and an internal jugular vein of the subject; and

configuring the current so as to reduce a heart condition of the subjectselected from the list consisting of: fibrosis of the heart, andinflammation of the heart.

For some applications, applying the current includes substantiallycontinuously applying the current. For some applications, applying thecurrent includes applying the current during an application periodlasting at least about three weeks, and configuring the current suchthat, during the application period, a longest duration of time in whichno current is applied is less than four hours. For some applications,applying the current includes applying the current for a period having aduration of more than about three weeks.

For some applications, the heart condition includes the fibrosis of theheart, and configuring the current includes configuring the current soas to reduce the fibrosis. Alternatively or additionally, the heartcondition includes the inflammation of the heart, and configuring thecurrent includes configuring the current so as to reduce theinflammation.

There is yet additionally provided, in accordance with an embodiment ofthe present invention, a method for treating a subject, including:

applying a current to a site of the subject selected from the listconsisting of: a vagus nerve of the subject, an epicardial fat pad ofthe subject, a pulmonary vein of the subject, a carotid artery of thesubject, a carotid sinus of the subject, a vena cava vein of thesubject, and an internal jugular vein of the subject; and

configuring the current to inhibit propagation of naturally-generatedefferent action potentials traveling through the site, while inhibitingno more than about 10% of naturally-generated afferent action potentialstraveling through the site, so as to treat a condition of the subject.

In an embodiment, the condition includes atrial fibrillation (AF), andconfiguring the current includes configuring the current so as to treatthe AF. In an embodiment, the condition includes bradycardia, andconfiguring the current includes configuring the current so as toprevent the bradycardia.

In an embodiment, the method includes administering to the subject adrug for treating the condition, and configuring the current includesconfiguring the current so as to increase an efficacy of the drug.

In an embodiment, configuring the current includes configuring thecurrent to have an amplitude of between about 0.1 and about 15milliamps. For some applications, configuring the current includesconfiguring the current to have an amplitude of between about 4 andabout 15 milliamps.

In an embodiment, applying the current includes applying the current inrespective bursts of pulses in each of a plurality of cardiac cycles ofthe subject. For some applications, configuring the current includesconfiguring each of the pulses to have a duration of between about 0.6and about 2 milliseconds. For some applications, configuring the currentincludes configuring the pulses within each of the bursts to have apulse repetition interval of between about 4 and about 20 milliseconds.

There is also provided, in accordance with an embodiment of the presentinvention, a method including:

selecting a subject who has not been diagnosed with any heart condition;

applying, for a period having a duration of at least about one month, acurrent to a site of the subject selected from the list consisting of: avagus nerve of the subject, an epicardial fat pad of the subject, apulmonary vein of the subject, a carotid artery of the subject, acarotid sinus of the subject, a vena cava vein of the subject, and aninternal jugular vein of the subject; and

configuring the current so as to not reduce a heart rate of the subjectbelow a normal heart rate for a typical human.

In an embodiment, the method includes sensing a heart rate of thesubject, and configuring the current includes configuring the current soas to reduce the heart rate towards the normal rate, responsive to adetermination that the heart rate is greater than the normal rate.

In an embodiment, the method includes sensing a heart rate of thesubject, and configuring the current includes configuring the current soas to minimize an effect of applying the current on the heart rate,responsive to a determination that the heart rate is within a desiredrange.

In an embodiment, the method includes sensing a physiological parameterof the subject, and configuring the current includes configuring thecurrent so as to reduce the heart rate towards the normal rate,responsive to the physiological parameter.

There is further provided, in accordance with an embodiment of thepresent invention, a method for treating a subject suffering from acondition, including:

applying a current to a site of the subject selected from the listconsisting of: a vagus nerve of the subject, and epicardial fat pad ofthe subject, a pulmonary vein of the subject, a carotid artery of thesubject, a carotid sinus of the subject, a vena cava vein of thesubject, and an internal jugular vein of the subject; and

configuring the current so as to delay electrical remodeling of anatrium of the subject caused by the condition.

In an embodiment, configuring the current includes configuring thecurrent so as to prevent electrical remodeling of the atrium caused bythe condition.

In an embodiment, the condition includes heart failure (HF), andconfiguring the current includes configuring the current so as toprevent the electrical remodeling caused by the HF.

In an embodiment, the condition includes both atrial fibrillation (AF)and heart failure (HF), and configuring the current includes configuringthe current so as to prevent the electrical remodeling caused by the AFand the HF.

In an embodiment, the method includes administering a drug for treatingthe condition.

In an embodiment, no drug is administered for treating the conditionduring a period beginning about 24 hours before initiation ofapplication of the current and ending upon the initiation of theapplication of the current.

In an embodiment, the condition includes atrial fibrillation (AF), andconfiguring the current includes configuring the current so as toprevent the electrical remodeling caused by the AF. For someapplications, applying the current includes detecting an occurrence ofthe AF, and applying the current responsively to the detecting. For someapplications, applying the current includes applying the current notresponsively to detecting an occurrence of the AF.

There is still further provided, in accordance with an embodiment of thepresent invention, a method for treating a subject susceptible tobradycardia, including:

administering to the subject a beta-blocker at a dosage lower than wouldnormally be indicated for the subject;

applying a current to a site of the subject selected from the listconsisting of: a vagus nerve of the subject, an epicardial fat pad ofthe subject, a pulmonary vein of the subject, a carotid artery of thesubject, a carotid sinus of the subject, a vena cava vein of thesubject, and an internal jugular vein of the subject;

sensing a heart rate of the subject; and

upon detecting an occurrence of the bradycardia, terminating applyingthe current at least until a cessation of the bradycardia.

In an embodiment, applying the current includes applying the current inrespective bursts of pulses in each of a plurality of cardiac cycles ofthe subject. For some applications, applying the current includesconfiguring each of the pulses to have a duration of between about 100microseconds and about 1 millisecond. For some applications, applyingthe current includes configuring each of the bursts to have a durationof between about 1 and about 60 milliseconds. For some applications,applying the current includes configuring each of the bursts to containbetween about 1 and about 5 pulses. For some applications, applying thecurrent includes configuring the pulses within each of the bursts tohave a pulse repetition interval of between about 1 and about 10milliseconds. For some applications, applying the current includesconfiguring the pulses to have an amplitude of between about 0.1 andabout 4 milliamps.

For some applications, applying the current includes applying the burstsonce every second heartbeat. For some applications, applying the currentincludes applying the current to the site intermittently duringalternating “on” and “off” periods, each of the “on” periods having aduration of at least about 500 milliseconds. For some applications,applying the current includes applying each of the bursts after a delayfollowing an R-wave of the subject, the delay having a duration ofbetween about 100 and about 700 milliseconds.

There is additionally provided, in accordance with an embodiment of thepresent invention, a method including:

applying a current to a site of a subject selected from the listconsisting of: a vagus nerve of the subject, an epicardial fat pad ofthe subject, a pulmonary vein of the subject, a carotid artery of thesubject, a carotid sinus of the subject, a vena cava vein of thesubject, and an internal jugular vein of the subject;

applying a pacing signal to a heart of the subject; and configuring thepacing signal to substantially prevent any heart-rate-lowering effectsof applying the current.

In an embodiment, applying the current includes applying the current tothe site intermittently during alternating “on” and “off” periods, andconfiguring the pacing signal includes configuring the pacing signal topace the heart at a rate that is approximately a rate of the heartduring the “off” periods.

In an embodiment, applying the pacing signal includes sensing apost-stimulation-initiation heart rate of the subject after initiatingapplication of the current, and applying the pacing signal when thepost-stimulation-initiation heart rate is less than a threshold heartrate. For some applications, the method includes sensing apre-stimulation-initiation heart rate of the subject prior to initiatingapplication of the current, and setting the threshold heart rate equalto the pre-stimulation-initiation heart rate.

In an embodiment, applying the pacing signal includes continuing toapply the pacing signal during a period following termination ofapplying the current. For some applications, the period has a durationof less than about 30 seconds, and continuing to apply the pacing signalincludes continuing to apply the pacing signal during the period havingthe duration of less than about 30 seconds.

There is yet additionally provided, in accordance with an embodiment ofthe present invention, a method including:

applying a current to a site of a subject selected from the listconsisting of: a vagus nerve of the subject, an epicardial fat pad ofthe subject, a pulmonary vein of the subject, a carotid artery of thesubject, a carotid sinus of the subject, a vena cava vein of thesubject, and an internal jugular vein of the subject; and

configuring the current to reduce mechanical tension on at least oneatrium of the subject, so as to reduce a risk of an occurrence of atrialfibrillation (AF).

In an embodiment, the method includes administering to the subject adrug for treating the AF.

There is also provided, in accordance with an embodiment of the presentinvention, a method for treating a subject suffering from an emergencycondition, including:

administering atropine to the subject so as to treat the emergencycondition;

applying a current to a site of the subject selected from the listconsisting of: a vagus nerve of the subject, an epicardial fat pad ofthe subject, a pulmonary vein of the subject, a carotid artery of thesubject, a carotid sinus of the subject, a vena cava vein of thesubject, and an internal jugular vein of the subject; and

configuring the current so as to reduce an adverse effect sometimescaused by the atropine.

There is further provided, in accordance with an embodiment of thepresent invention, a method for treating a subject, including:

applying a current to a site of the subject selected from the listconsisting of: a vagus nerve of the subject, an epicardial fat pad ofthe subject, a pulmonary vein of the subject, a carotid artery of thesubject, a carotid sinus of the subject, a vena cava vein of thesubject, and an internal jugular vein of the subject; and

configuring the current so as to treat a condition of the subjectselected from the list consisting of: an autoimmune disease, anautoimmune inflammatory disease, multiple sclerosis, encephalitis,myelitis, immune-mediated neuropathy, myositis, dermatomyositis,polymyositis, inclusion body myositis, inflammatory demyelinatingpolyradiculoneuropathy, Guillain Barre syndrome, myasthenia gravis,inflammation of the nervous system, inflammatory bowel disease, Crohn'sdisease, ulcerative colitis, SLE (systemic lupus erythematosus),rheumatoid arthritis, vasculitis, polyarteritis nodosa, Sjogrensyndrome, mixed connective tissue disease, glomerulonephritis, thyroidautoimmune disease, sepsis, meningitis, a bacterial infection, a viralinfection, a fungal infection, sarcoidosis, hepatitis, and portal veinhypertension.

In an embodiment, the control unit is adapted to monitor a heart rate ofthe subject, and withhold the applying of the current in response to theheart rate being lower than a threshold heart rate.

There is still further provided, in accordance with an embodiment of thepresent invention, a method for treating a subject, including:

applying a current to a site of the subject selected from the listconsisting of: a vagus nerve of the subject, and epicardial fat pad ofthe subject, a pulmonary vein of the subject, a carotid artery of thesubject, a carotid sinus of the subject, a vena cava vein of thesubject, and an internal jugular vein of the subject; and

configuring the current so as to have an antiarrhythmic effect on anatrium of the subject.

For some applications, the site includes a right vagus nerve of thesubject, and applying the current includes applying the current to theright vagus nerve.

In an embodiment, the method includes administering an antiarrhythmicdrug to the subject in conjunction with applying the current.

For some applications, configuring the current includes configuring thecurrent so as to induce rhythmic vagal activity in the subject.

There is additionally provided, in accordance with an embodiment of thepresent invention, a method for treating a subject suffering from heartfailure (HF), including:

applying a current to a site of the subject selected from the listconsisting of: a vagus nerve of the subject, an epicardial fat pad ofthe subject, a pulmonary vein of the subject, a carotid artery of thesubject, a carotid sinus of the subject, a vena cava vein of thesubject, and an internal jugular vein of the subject; and

configuring the current so as to decrease atrial contractile force of aheart of the subject, so as to treat the HF.

In an embodiment, applying the current includes applying the current tothe site intermittently during alternating “on” and “off” periods. Forsome applications, applying the current intermittently includes settingeach of the “on” periods to have a duration of between about 1 and about15 seconds, and each of the “off” periods to have a duration of betweenabout 5 and about 20 seconds.

In an embodiment, the site includes the vagus nerve, and applying thecurrent includes applying the current to the vagus nerve. For someapplications, applying the current includes applying a stimulatingcurrent, which is capable of inducing action potentials in a first setand a second set of nerve fibers of the vagus nerve, and an inhibitingcurrent, which is capable of inhibiting the induced action potentialstraveling in the second set of nerve fibers, the nerve fibers in thesecond set having generally larger diameters than the nerve fibers inthe first set. For some applications, applying the current includesapplying a stimulating current, which is capable of inducing actionpotentials in the vagus nerve, and an inhibiting current, which iscapable of inhibiting action potentials induced by the stimulatingcurrent and traveling in the vagus nerve in an afferent direction towarda brain of the subject.

In an embodiment, applying the current includes applying the current inrespective bursts of pulses in each of a plurality of cardiac cycles ofthe subject. For some applications, applying the current includesapplying a first pulse of each of the bursts after a delay from a sensedfeature of an electrocardiogram (ECG) of the subject.

In an embodiment, the method includes sensing a physiological parameterof the subject, and configuring the current includes configuring thecurrent at least in part responsively to the sensed physiologicalparameter. For some applications, sensing the physiological parameterincludes sensing a heart rate of the subject.

In an embodiment, configuring the current includes configuring thecurrent so as to minimize an effect of the applying of the current on aheart rate of the subject.

In an embodiment, applying the current includes applying the current inrespective bursts of pulses in each of a plurality of cardiac cycles ofthe subject. For some applications, applying the current includesapplying the current to a left vagus nerve of the subject. For someapplications, applying the current includes configuring each of thepulses to have a duration of between about 200 microseconds and about2.5 milliseconds. For some applications, applying the current includesconfiguring each of the pulses to have a duration of between about 2.5and about 5 milliseconds. For some applications, applying the currentincludes configuring each of the bursts to have a duration of betweenabout 0.2 and about 40 milliseconds. For some applications, applying thecurrent includes configuring each of the bursts to contain between about1 and about 10 pulses. For some applications, applying the currentincludes configuring the pulses within each of the bursts to have apulse repetition interval of between about 2 and about 10 milliseconds.For some applications, applying the current includes configuring thepulses to have an amplitude of between about 0.5 and about 5 milliamps.For some applications, applying the current includes applying the burstsless than every heartbeat of the subject. For some applications,applying the current includes applying the bursts once per heartbeat ofthe subject. For some applications, applying the current includesapplying the current to the site intermittently during alternating “on”and “off” periods, each of the “on” periods having a duration of atleast about 1 second. For some applications, applying the currentincludes applying each of the bursts after a variable delay following aP-wave of the subject, the delay having a duration equal to betweenabout two-thirds and about 90% of a duration of a cardiac cycle of thesubject. For some applications, applying the current includessubstantially continuously measuring the duration of the cardiac cycle.

In an embodiment, applying the current includes applying the current inrespective bursts of pulses in each of a plurality of cardiac cycles ofthe subject. For some applications, applying the current includesconfiguring each of the pulses to have a duration of between about 100microseconds and about 2.5 milliseconds. For some applications, applyingthe current includes configuring each of the bursts to have a durationof between about 1 and about 180 milliseconds. For some applications,applying the current includes configuring each of the bursts to containbetween about 1 and about 10 pulses. For some applications, applying thecurrent includes configuring the pulses within each of the bursts tohave a pulse repetition interval of between about 1 and about 20milliseconds. For some applications, applying the current includesconfiguring the pulses to have an amplitude of between about 0.1 andabout 9 milliamps. For some applications, applying the current includesapplying the bursts once every second heartbeat. For some applications,applying the current includes applying the bursts once every thirdheartbeat. For some applications, applying the current includes applyingthe current to the site intermittently during alternating “on” and “off”periods, each of the “on” periods having a duration of at least about 1second. For some applications, applying the current includes applyingeach of the bursts after a delay following an R-wave of the subject, thedelay having a duration of about 100 milliseconds.

In an embodiment, applying the current includes applying the current inrespective bursts of between about 1 and about 10 pulses in each of aplurality of cardiac cycles of the subject, and applying a first pulseof each of the bursts after a delay of about 100 milliseconds after asensed R-wave of an electrocardiogram (ECG) of the subject. For someapplications, applying the current includes configuring each of thebursts to contain about three pulses. For some applications, applyingthe current includes varying a number of the pulses in each of thebursts responsive to a sensed parameter of a respiratory cycle of thesubject. For some applications, applying the current includes varying anumber of the pulses in each of the bursts responsive to a sensed heartrate of the subject. For some applications, the site includes the vagusnerve, and applying the current includes applying the current to thevagus nerve, and, responsive to a sensed heart rate of the subject,varying a number of nerve fibers of the vagus nerve that are recruited.

For some applications, the site includes the vagus nerve, and applyingthe current includes applying the current to the vagus nerve, and,responsive to a sensed parameter of a respiratory cycle of the subject,varying a number of nerve fibers of the vagus nerve that are recruited.For some applications, applying the current includes cycling between afirst set of parameters and a second set of parameters. For someapplications, cycling includes applying each set of parameters for lessthan about 15 seconds. For some applications, cycling includes applyingeach set of parameters for between about 1 and about 4 seconds. For someapplications, the first set of parameters includes a first amplitude,the second set of parameters includes a second amplitude, greater thanthe first amplitude, and applying the current includes varying a numberof nerve fibers of the vagus nerve that are recruited by cycling betweenthe first set of parameters and the second set of parameters.

For some applications, cycling includes synchronizing application of thefirst set of parameters with inhalation by the subject, andsynchronizing application of the second set of parameters withexhalation by the subject. For some applications, at least one of thefirst and second sets of parameters includes a pulse repetition intervalof between about 4 and about 20 milliseconds, and applying the currentincludes cycling between the first and second sets of parameters. Forsome applications, at least one of the first and second sets ofparameters includes a pulse width of between about 0.1 and about 2milliseconds, and applying the current includes cycling between thefirst and second sets of parameters. For some applications, the firstset of parameters includes application of the current at one pulse pereach of the bursts, the second set of parameters includes application ofthe current at about three pulses per each of the bursts, and applyingthe current includes cycling between the first and second sets ofparameters.

There is yet additionally provided, in accordance with an embodiment ofthe present invention, apparatus for treating a subject, including:

an electrode device, adapted to be coupled to a site of the subjectselected from the list consisting of: a vagus nerve of the subject, anepicardial fat pad of the subject, a pulmonary vein of the subject, acarotid artery of the subject, a carotid sinus of the subject, a venacava vein of the subject, and an internal jugular vein of the subject;and

a control unit, adapted to:

drive the electrode device to apply an electrical current to the site,and

configure the current so as to enhance an efficacy of a drugadministered to the subject for treating a condition from which thesubject suffers selected from the list consisting of: atrialfibrillation (AF) and heart failure (HF).

There is also provided, in accordance with an embodiment of the presentinvention, a system for treating a subject, including:

a drug, adapted to be administered to the subject, and to treat acondition from which the subject suffers selected from the listconsisting of: atrial fibrillation (AF) and heart failure (HF); and

apparatus including:

-   -   an electrode device, adapted to be coupled to a site of the        subject selected from the list consisting of: a vagus nerve of        the subject, an epicardial fat pad of the subject, a pulmonary        vein of the subject, a carotid artery of the subject, a carotid        sinus of the subject, a vena cava vein of the subject, and an        internal jugular vein of the subject; and    -   a control unit, adapted to:    -   drive the electrode device to apply an electrical current to the        site, and    -   configure the current so as to enhance an efficacy of the drug.

There is further provided, in accordance with an embodiment of thepresent invention, apparatus for treating a subject suffering from acondition, including:

an electrode device, adapted to be coupled to a site of the subjectselected from the list consisting of: a vagus nerve of the subject, anepicardial fat pad of the subject, a pulmonary vein of the subject, acarotid artery of the subject, a carotid sinus of the subject, a venacava vein of the subject, and an internal jugular vein of the subject;and

a control unit, adapted to:

drive the electrode device to apply an electrical current to the site,and

configure the current to increase vagal tone of the subject, and tominimize an effect of applying the current on a heart rate of thesubject, so as to treat the condition.

There is still further provided, in accordance with an embodiment of thepresent invention, apparatus for treating a subject suffering from acondition, including:

an electrode device, adapted to be coupled to a site of the subjectselected from the list consisting of: a vagus nerve of the subject, anepicardial fat pad of the subject, a pulmonary vein of the subject, acarotid artery of the subject, a carotid sinus of the subject, a venacava vein of the subject, and an internal jugular vein of the subject;and

a control unit, adapted to:

drive the electrode device to apply an electrical current to the site,and

configure the current so as to reduce an adverse effect sometimes causedby a drug administered to the subject for treating the condition.

There is additionally provided, in accordance with an embodiment of thepresent invention, a system for treating a subject suffering from acondition, including:

a drug, adapted to be administered to the subject, and to treat thecondition; and

apparatus including:

-   -   an electrode device, adapted to be coupled to a site of the        subject selected from the list consisting of: a vagus nerve of        the subject, an epicardial fat pad of the subject, a pulmonary        vein of the subject, a carotid artery of the subject, a carotid        sinus of the subject, a vena cava vein of the subject, and an        internal jugular vein of the subject; and    -   a control unit, adapted to:    -   drive the electrode device to apply an electrical current to the        site, and    -   configure the current so as to reduce an adverse effect        sometimes caused by the drug.

There is yet additionally provided, in accordance with an embodiment ofthe present invention, apparatus for treating a subject, including:

an electrode device, adapted to be coupled to a site of the subjectselected from the list consisting of: a vagus nerve of the subject, anepicardial fat pad of the subject, a pulmonary vein of the subject, acarotid artery of the subject, a carotid sinus of the subject, a venacava vein of the subject, and an internal jugular vein of the subject;and

a control unit, adapted to:

drive the electrode device to apply an electrical current to the site,and

configure the current so as to reduce a heart condition of the subjectselected from the list consisting of: fibrosis of the heart, andinflammation of the heart.

For some applications, in an operating mode of the control unit, thecontrol unit is adapted to drive the electrode device to apply thecurrent during an application period lasting at least about three weeks,and to configure the current such that, during the application period, alongest duration of time in which no current is applied is less thanfour hours.

There is also provided, in accordance with an embodiment of the presentinvention, apparatus for treating a subject, including:

an electrode device, adapted to be coupled to a site of the subjectselected from the list consisting of: a vagus nerve of the subject, anepicardial fat pad of the subject, a pulmonary vein of the subject, acarotid artery of the subject, a carotid sinus of the subject, a venacava vein of the subject, and an internal jugular vein of the subject;and

a control unit, adapted to:

drive the electrode device to apply an electrical current to the site,and

configure the current to inhibit propagation of naturally-generatedefferent action potentials traveling through the site, while inhibitingno more than about 10% of naturally-generated afferent action potentialstraveling through the site, so as to treat a condition of the subject.

There is further provided, in accordance with an embodiment of thepresent invention, apparatus for treating a subject who has not beendiagnosed with any heart condition, including:

an electrode device, adapted to be coupled to a site of the subjectselected from the list consisting of: a vagus nerve of the subject, anepicardial fat pad of the subject, a pulmonary vein of the subject, acarotid artery of the subject, a carotid sinus of the subject, a venacava vein of the subject, and an internal jugular vein of the subject;and

a control unit, adapted to:

drive the electrode device to apply an electrical current to the sitefor a period having a duration of at least about one month, and

configure the current so as to not reduce a heart rate of the subjectbelow a normal heart rate for a typical human.

There is still further provided, in accordance with an embodiment of thepresent invention, apparatus for treating a subject suffering from acondition, including:

an electrode device, adapted to be coupled to a site of the subjectselected from the list consisting of: a vagus nerve of the subject, anepicardial fat pad of the subject, a pulmonary vein of the subject, acarotid artery of the subject, a carotid sinus of the subject, a venacava vein of the subject, and an internal jugular vein of the subject;and

a control unit, adapted to:

drive the electrode device to apply an electrical current to the site,and

configure the current so as to delay electrical remodeling of an atriumof the subject caused by the condition.

There is additionally provided, in accordance with an embodiment of thepresent invention, apparatus including:

a pacemaker, adapted to be coupled to a heart of a subject;

an electrode device, adapted to be coupled to a site of the subjectselected from the list consisting of: a vagus nerve of the subject, anepicardial fat pad of the subject, a pulmonary vein of the subject, acarotid artery of the subject, a carotid sinus of the subject, a venacava vein of the subject, and an internal jugular vein of the subject;and

a control unit, adapted to:

drive the electrode device to apply an electrical current to the site,

drive the pacemaker to apply a pacing signal to the heart, and

configure the pacing signal to substantially prevent anyheart-rate-lowering effects of applying the current.

There is also provided, in accordance with an embodiment of the presentinvention, apparatus including:

an electrode device, adapted to be coupled to a site of a subjectselected from the list consisting of: a vagus nerve of the subject, anepicardial fat pad of the subject, a pulmonary vein of the subject, acarotid artery of the subject, a carotid sinus of the subject, a venacava vein of the subject, and an internal jugular vein of the subject;and

a control unit, adapted to:

drive the electrode device to apply an electrical current to the site,and

configure the current to reduce mechanical tension on at least oneatrium of the subject, so as to reduce a risk of an occurrence of atrialfibrillation (AF).

There is further provided, in accordance with an embodiment of thepresent invention, apparatus for treating a subject, including:

an electrode device, adapted to be coupled to a site of the subjectselected from the list consisting of: a vagus nerve of the subject, anepicardial fat pad of the subject, a pulmonary vein of the subject, acarotid artery of the subject, a carotid sinus of the subject, a venacava vein of the subject, and an internal jugular vein of the subject;and

a control unit, adapted to:

drive the electrode device to apply an electrical current to the site,and

configure the current so as to treat a condition of the subject selectedfrom the list consisting of: an autoimmune disease, an autoimmuneinflammatory disease, multiple sclerosis, encephalitis, myelitis,immune-mediated neuropathy, myositis, dermatomyositis, polymyositis,inclusion body myositis, inflammatory demyelinatingpolyradiculoneuropathy, Guillain Barre syndrome, myasthenia gravis,inflammation of the nervous system, inflammatory bowel disease, Crohn'sdisease, ulcerative colitis, SLE (systemic lupus erythematosus),rheumatoid arthritis, vasculitis, polyarteritis nodosa, Sjogrensyndrome, mixed connective tissue disease, glomerulonephritis, thyroidautoimmune disease, sepsis, meningitis, a bacterial infection, a viralinfection, a fungal infection, sarcoidosis, hepatitis, and portal veinhypertension.

There is still further provided, in accordance with an embodiment of thepresent invention, apparatus for treating a subject, including:

an electrode device, adapted to be coupled to a site of the subjectselected from the list consisting of: a vagus nerve of the subject, anepicardial fat pad of the subject, a pulmonary vein of the subject, acarotid artery of the subject, a carotid sinus of the subject, a venacava vein of the subject, and an internal jugular vein of the subject;and

a control unit, adapted to:

drive the electrode device to apply an electrical current to the site,and

configure the current so as to have an antiarrhythmic effect on anatrium of the subject.

There is additionally provided, in accordance with an embodiment of thepresent invention, apparatus for treating a subject suffering from heartfailure (HF), including:

an electrode device, adapted to be coupled to a site of the subjectselected from the list consisting of: a vagus nerve of the subject, anepicardial fat pad of the subject, a pulmonary vein of the subject, acarotid artery of the subject, a carotid sinus of the subject, a venacava vein of the subject, and an internal jugular vein of the subject;and

a control unit, adapted to:

drive the electrode device to apply an electrical current to the site,and

configure the current so as to decrease atrial contractile force of aheart of the subject, so as to treat the HF.

The present invention will be more fully understood from the followingdetailed description of embodiments thereof, taken together with thedrawings, in which:

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a schematic illustration of apparatus for treating a patient,in accordance with an embodiment of the present invention;

FIG. 2A is a simplified cross-sectional illustration of a multipolarelectrode device applied to a vagus nerve, in accordance with anembodiment of the present invention;

FIG. 2B is a simplified perspective illustration of the electrode deviceof FIG. 2A, in accordance with an embodiment of the present invention;

FIG. 3 is a simplified perspective illustration of a multipolar pointelectrode device applied to a vagus nerve, in accordance with anembodiment of the present invention;

FIG. 4 is a conceptual illustration of the application of current to avagus nerve, in accordance with an embodiment of the present invention;

FIG. 5 is a simplified illustration of an electrocardiogram (ECG)recording and of example timelines showing the timing of the applicationof a series of stimulation pulses, in accordance with an embodiment ofthe present invention;

FIGS. 6 and 7 are graphs showing in vivo experimental results measuredin accordance with an embodiment of the present invention;

FIG. 8 is a chart showing in vivo experimental results in accordancewith an embodiment of the present invention;

FIGS. 9A and 9B are graphs showing an analysis of the experimentalresults of the experiment of FIG. 7, in accordance with an embodiment ofthe present invention; and

FIGS. 10A and 10B are graphs showing in vivo experimental results inaccordance with an embodiment of the present invention.

DETAILED DESCRIPTION OF EMBODIMENTS

FIG. 1 is a schematic illustration of apparatus 20 for treating apatient 30, in accordance with an embodiment of the present invention.Apparatus 20 comprises at least one electrode device 22, which isapplied to a vagus nerve 24 (either a left vagus nerve 25 or a rightvagus nerve 26), which innervates a heart 28 of patient 30. Apparatus 20further comprises an implanted or external control unit 32, whichtypically communicates with electrode device 22 over a set of leads 33.For some applications, apparatus 20 comprises two electrode devices 22,one of which is applied to left vagus nerve 25, and the other to rightvagus nerve 26.

For some applications, as described hereinbelow, control unit 32 isadapted to drive electrode device 22 to apply signals to vagus nerve 26.The control unit configures these signals to induce the propagation ofefferent nerve impulses towards heart 28. The control unit typicallyconfigures the signals based on the particular application, by settingone or more parameters of the signals, such as:

-   -   frequency of pulses within a pulse burst, e.g., for n pulses        during a burst lasting t milliseconds, the burst has a frequency        of 1000 n/t Hz;    -   amplitude;    -   pulse width;    -   number of pulse delivered per heartbeat (pulses per trigger, or        PPT);    -   duty cycle;    -   pulse polarity; and    -   timing within the cardiac cycle.

Control unit 32 is typically adapted to receive and analyze one or moresensed physiological parameters or other parameters of patient 30, suchas ventricular and/or atrial rate, electrocardiogram (ECG), bloodpressure, indicators of decreased cardiac contractility, cardiac output,norepinephrine concentration, baroreflex sensitivity, or motion of thepatient. In order to receive these sensed parameters, control unit 32may comprise, for example, an ECG monitor 38, connected to a site on thepatient's body such as heart 28, for example using one or moresubcutaneous sensors or ventricular and/or atrial intracardiac sensors.The control unit may also comprise an accelerometer 39 for detectingmotion of the patient. Alternatively, ECG monitor 38 and/oraccelerometer 39 comprise separate implanted devices placed external tocontrol unit 32, and, optionally, external to the patient's body.Alternatively or additionally, control unit 32 receives signals from oneor more physiological sensors 40, such as blood pressure sensors. Forsome applications, control unit 32 comprises or is coupled to animplantable cardioverter defibrillator (ICD) 41 and/or a pacemaker 42(e.g., a bi-ventricular or standard pacemaker).

For some applications, control unit 32 is adapted to distinguish betweenAF and NSR, generally by analyzing an ECG signal generated by ECGmonitor 38. In order to detect rapid atrial activity indicative of AF,the analysis may include one or more of the following:

-   -   P-wave analysis;    -   analysis of ventricular response rate and/or ventricular        response variability;    -   sensed pressure, such as atrial pressure, sensed venous        pressure, and/or sensed arterial pressure;    -   the relationship(s) between one or more of the sensed pressures        and sensed ventricular contractions (in the case of arterial        pressure, such relationship is an indication of pulse deficit);        and/or    -   analysis of the duration of the isoelectrical segment of the        ECG, optionally using the technique described in the above-cited        article by Wijffels et al., entitled, “Atrial fibrillation        begets atrial fibrillation.” A duration greater than a first        threshold value is typically indicative of NSR, while a duration        less than a second threshold value, the second threshold value        less than or equal to the first threshold value, is typically        indicative of AF.

Control unit 32 itself may perform this analysis, or it may transmitdata for analysis by an external processor (not shown).

Typically, apparatus 20 is programmable by a physician, such as by usingan external console wirelessly in communication with control unit 32.The apparatus typically provides notification of various occurrences,such as the initiation of AF, the initiation of treatment, or amechanical failure. The apparatus may provide such notifications byvarious means, including generating a tone, vibrating, and/or wirelesslycommunicating with a local or remote receiver, such as one located at amedical facility.

For some applications of vagal stimulation, control unit 32 applies thesignals to vagus nerve 24 as a burst of pulses during each cardiaccycle, with one or more of the following parameters (collectively, theseparameters are referred to hereinbelow as “typical stimulationparameters”):

-   -   Timing of the stimulation: for example, each pulse may be        initiated at about 100 milliseconds after an R-wave.    -   Pulse duration: each pulse typically has a duration of between        about 100 microseconds and about 2.5 milliseconds, e.g., about 1        millisecond.    -   Pulse amplitude: the pulses are typically applied with an        amplitude of between about 0.1 and about 9 milliamps, e.g.,        about 2.5 milliamps.    -   Pulse repetition interval: the pulses within the burst of pulses        typically have a pulse repetition interval (the time from the        initiation of a pulse to the initiation of the following pulse)        of between about 1 and about 20 milliseconds, e.g., about 6        milliseconds.    -   Pulses per trigger (PPT): the burst of pulses typically contains        between about 1 and about 10 pulses, e.g., 3 pulses.    -   Pulse period, i.e., burst duration (equal to the product of        pulse repetition interval and PPT): the burst of pulses        typically has a total duration of between about 1 and about 180        milliseconds.    -   Duty cycle: stimulation is typically applied once per heartbeat,        once every second heartbeat, or once every third heartbeat.    -   On/off status: for some applications, stimulation is always        “on”, i.e., constantly applied (in which case, parameters closer        to the lower ends of the ranges above are typically used). For        other applications, on/off cycles vary between a few seconds to        several minutes, e.g., “on” for 15 seconds, “off” for 60        seconds.

In an embodiment of the present invention, a method for enhancing orsustaining the efficacy of drug treatment for atrial fibrillation (AF)comprises administering a drug to patient 30 and applying signals to avagus nerve that innervates heart 28 of the patient. The drugadministered typically includes either:

-   -   a sinus rhythm maintenance drug (i.e., an antiarrhythmic drug),        such as a beta-blocker, digoxin, amiodarone, disopyramide,        dofetilide, a class IC drug (e.g., flecainide, propafenone),        procainamide, quinidine, or sotalol; or    -   a ventricular rate control drug, such as a beta-blocker (e.g.,        esmolol), calcium channel antagonists (e.g., verapamil,        diltiazem), or digoxin.

According to this method, the efficacy of the drug is typically enhancedor sustained by (a) configuring the signals so as to prevent electricalremodeling of the atria, which remodeling generally reduces drugeffectiveness over time, (b) configuring the signals so as to achieve atherapeutic benefit similar to that of the drug, which typically resultsin a synergistic effect between the therapeutic benefit of the drug andthe vagal stimulation, and/or (c) configuring the signals so as toreduce the mechanical tension on the atria.

Atrial electrical remodeling, i.e., electrophysiological changes to theatria, commonly occurs in patients suffering from AF. Such electricalremodeling is believed to be caused by the underlying heart conditionthat instigated the AF, and/or by the effect of the AF itself on theatria (see the above-cited article entitled, “Atrial fibrillation begetsatrial fibrillation,” by Wijffels et al.). As electrical remodelingbecomes more severe, relapses into AF become more frequent and difficultto prevent. As a result, drug therapy for preventing such relapsesbecomes less effective. Vagal stimulation, using techniques describedherein, typically delays or prevents (i.e., delays indefinitely)electrical remodeling, thereby prolonging the effectiveness ofantiarrhythmic drugs. For some applications, control unit 32 configuresthe signals applied to the vagus nerve using parameters describedhereinbelow for applying vagal stimulation with minimum heart ratereduction.

In an embodiment of the present invention, vagal stimulation is appliedin combination with administration of a drug, as described in thefollowing examples:

In Combination with Beta-blockers

A beta-blocker is administered substantially at its usual dosage (i.e.,at a dosage determined independently of applying the vagal stimulation),and vagal stimulation is applied using parameters described hereinbelowfor applying vagal stimulation with minimum heart rate reduction.

For Bradycardia

For treating a patient susceptible to bradycardia, a beta-blocker isadministered at a dosage lower than would normally be indicated, andvagal stimulation is applied using parameters described hereinbelow forapplying vagal stimulation with minimum heart rate reduction, or usingparameters at the lower range of the typical stimulation parametersdescribed hereinabove. Upon detection of bradycardia, the vagalstimulation is terminated.

In Combination with a Sinus Rhythm Maintenance Drug

A patient who suffers from AF is treated by conventional cardioversionand a sinus rhythm maintenance drug, such as quinidine. To enhance thedesired effect of the drug, the drug is administered in conjunction withthe application of rhythmic vagal stimulation. The resulting rhythmic,synchronized vagal activity generally mimics normal vagal traffic, whichis sometimes reduced in these patients (who may, for example, sufferfrom heart failure or hypertension). Stable NSR typically results fromthe combined treatment modalities, thereby generally reducing theoccurrence of AF.

Parameters of such rhythmic vagal stimulation typically include all orsome of the following: (a) application of the stimulation as burstssynchronized with the patient's cardiac cycle, with each burst typicallybeginning at about 100 milliseconds after an R-wave, (b) about threepulses per burst (i.e., per cardiac cycle), (c) varying the number ofpulses per burst responsive to sensed parameters of the patient'srespiratory cycle or heart rate, and (d) varying the number of nervefibers recruited responsive to sensed parameters of the patient'srespiratory cycle or heart rate.

For example, vagal stimulation may be applied by cycling between a firstset and a second set of parameters, applying each set for less thanabout 15 seconds, e.g., for between about 1 and about 4 seconds. Thefirst set of parameters may include: (a) a low amplitude, e.g., 2milliamps, so as to recruit a relatively small number of nerve fibers,(b) optional synchronization with inhalation, and (c) one pulse pertrigger (PPT), for example applied at about 300 milliseconds after anR-wave. The second set of parameters may include: (a) a greateramplitude, e.g., 3 milliamps, so as to recruit a greater number offibers, (b) optional synchronization with exhalation, and (c) three PPT,applied at about 300 milliseconds after an R-wave. Both sets ofparameters optionally include a pulse width of about 1 millisecondand/or a pulse repetition interval of between about 4 and about 20milliseconds.

In Combination with a Positive Inotropic Agent

A positive inotropic agent is administered for longer than one day, andvagal stimulation is applied using techniques described herein, usingthe typical stimulation parameters described hereinabove. Without theuse of the vagal stimulation techniques described herein, drugs of thisclass (with the exception of digitalis) are generally administered onlyin an acute setting. In combination with vagal stimulation as describedherein, however, the administration of the positive inotropic agent ishypothesized by the inventors to have the same or enhanced effect,without its chronotropic and proarrhythmic (ventricular) effects. Inaddition, it is hypothesized that in combination with vagal stimulationas described herein, the positive effects of the positive inotropicagent do not decline, or decline less, over time, when administered on along-term basis.

For treating a stable patient, a positive inotropic agent isadministered, and vagal stimulation is applied using parametersdescribed hereinbelow for applying vagal stimulation with minimum heartrate reduction, or using the typical stimulation parameters describedhereinabove. Without the use of the vagal stimulation techniquesdescribed herein, drugs of this class are generally not routinely usedbecause of evidence indicating increased mortality mainly attributableto ventricular arrhythmia. Use of the vagal stimulation techniquesdescribed herein typically reduces the incidence of ventriculararrhythmia, thereby enabling the use of drugs of this class forlonger-term treatment of stable patients.

For Emergency Settings

In order to increase heart rate in an emergency setting (e.g.,bradycardia and/or shock), atropine is administered, and vagalstimulation is applied, using the typical stimulation parametersdescribed hereinabove, in order to increase heart rate and cardiacoutput.

In Combination with a Class IC Drug

A class IC drug is administered at a dosage greater than would normallybe indicated or considered safe, and vagal stimulation is applied usingparameters described hereinbelow for applying vagal stimulation withminimum heart rate reduction, or using the typical stimulationparameters described hereinabove, to counteract at least some of theside effects of the class IC drug.

In an embodiment of the present invention, vagal stimulation configuredfor inhibiting, delaying or preventing (i.e., delaying indefinitely)electrical remodeling in AF patients is applied in the absence ofspecific antiarrhythmic drug therapy. Such prevention of electricalremodeling alone is believed by the inventors to be therapeuticallybeneficial. For example, Takei et al., in their above-cited article,hypothesize, based on their experiments in anesthetized dogs, that vagalstimulation prior to atrial rapid pacing may protect the atrium fromelectrical remodeling.

In an embodiment of the present invention, a method for enhancing orsustaining the efficacy of a drug treatment for AF comprisesadministering a drug to the patient, applying signals to the vagusnerve, and configuring the signals to reduce the mechanical tension onthe atria. Such reduced mechanical tension generally reduces the risk ofAF. For some applications, such vagal stimulation is applied withoutadministering the drug.

For some applications, such vagal stimulation for the prevention ofatrial remodeling (whether or not in conjunction with drug therapy) isapplied generally constantly, using parameters described hereinbelow forapplying vagal stimulation with minimum heart rate reduction, or usingthe typical stimulation parameters described hereinabove. For otherapplications, such stimulation is only applied upon the detection of theoccurrence of AF, such as by using one or more of the AF detectiontechniques described hereinabove.

In an embodiment of the present invention, control unit 32 configuresthe signals applied to the vagus nerve to have an antiarrhythmic effecton the atrium. Typical signal parameters in such a configuration includethose described hereinbelow for applying vagal stimulation with minimumheart rate reduction, or the typical stimulation parameters describedhereinabove. The stimulation is typically applied to right vagus nerve26, but may also be applied to left vagus nerve 25 or both vagus nervestogether. For some applications, such antiarrhythmic vagal stimulationis applied in conjunction with the rhythmic vagal stimulation techniquedescribed hereinabove. For applications in which such antiarrhythmicvagal stimulation is applied in combination with antiarrhythmic drugtherapy, the combined treatment generally results in a synergisticeffect.

In another embodiment of the present invention, the effectiveness ofventricular rate control drugs is typically enhanced by applying vagalstimulation in order to control the ventricular response rate. Suchcombined vagal stimulation and drug therapy generally results in asynergistic effect. Vagal stimulation techniques for controllingventricular response rate may be used that are described in U.S. patentapplication Ser. No. 10/205,475, filed Jul. 24, 2002, entitled,“Selective nerve fiber stimulation for treating heart conditions,” whichis assigned to the assignee of the present patent application and isincorporated herein by reference, or by using other techniques known inthe art.

In an embodiment of the present invention, the safety of a drugadministered to patient 30 is improved by applying signals to vagusnerve 24, and configuring the signals so as to prevent adverse effectssometimes caused by the drug, such as repolarization abnormalities(e.g., prolongation of the QT interval), bradycardia, and/or ventriculartachyarrhythmia (e.g., ventricular fibrillation). In some cases, thedrug can safely be administered to patients who otherwise could nottolerate the drug because of such adverse effects. (See, for example,the above-cited article by Kwan et al., which discusses the limitationsside effects sometimes impose on drug success). In addition, in somecases adverse effects of the drug are prevented or diminished byallowing the use of lower dosages of the drug (i.e., dosages lower thandosages determined independently of applying the vagal stimulation), byenhancing or sustaining the efficacy of the drug, as describedhereinabove. For example, toxicity associated with digoxin may beprevented or reduced by enabling a lower dosage using these stimulationtechniques.

Prolongation of the QT interval is an adverse effect sometimes caused byantiarrhythmic drugs. Vagal stimulation, using techniques describedherein, typically shortens the QT interval, thereby offsetting the QTprolongation caused by such drugs. As a result, such drugs are generallysafer, and, in some cases, more effective. In addition, such increasedsafety allows for the use of higher dosages of such drugs, iftherapeutically indicated. For some applications, in order to obtain theQT interval reduction, and/or to prevent other side effects, such asabdominal pain, diarrhea, or ventricular arrhythmia not related to theQT interval, control unit 32 configures the signals applied to the vagusnerve using parameters described hereinbelow for applying vagalstimulation with minimum heart rate reduction.

Bradycardia is an adverse effect sometimes caused by antiarrhythmicdrugs and heart rate control drugs. The use of a lower dosage of suchdrugs enabled by vagal stimulation techniques described herein generallyreduces the likelihood of bradycardia, while obtaining a beneficialeffect similar to that achieved at higher drugs dosages without suchvagal stimulation. This vagal stimulation is typically applied usingtechniques described herein for minimizing reductions in heart rate as aresult of the stimulation. In addition, in an embodiment, apparatus 20monitors heart rate, such as by using ECG monitor 38, and, upondetection of bradycardia, activates pacemaker 42 to pace the heart.Alternatively or additionally, upon detection of bradycardia, apparatus20 terminates or reduces the intensity of vagal stimulation.

Ventricular tachyarrhythmia is an adverse effect sometimes caused byantiarrhythmic drugs or positive inotropic drugs. Vagal stimulation,using techniques described herein, typically reduces or preventstachyarrhythmia, premature ventricular contractions, ventriculartachycardia, accelerated idioventricular arrhythmia, and/or ventricularfibrillation, by reducing the propensity of cardiac tissue tospontaneously fire.

In an embodiment of the present invention, a method for enhancing orsustaining the efficacy of drug treatment for heart failure comprisesadministering a drug to patient 30 and applying signals to vagus nerve24 that innervates heart 28 of the patient. The signals are configuredso as to treat the heart failure, which typically results in asynergistic effect between the therapeutic benefit of the drug and thevagal stimulation. For example, the drug may include positive inotropicdrugs such as digoxin, dopamine, dobutamine, adrenaline, amrinone, ormilrinone.

Alternatively or additionally, the signals are configured so as toprevent adverse effects sometimes caused by the heart failure drug, suchas ventricular arrhythmia and/or ventricular tachycardia. For someapplications, ventricular tachycardia is prevented using techniquesdescribed hereinabove for controlling ventricular response rate usingvagal stimulation. For some applications, arrhythmia is prevented byelevation of vagal tone and application of rhythmic synchronized vagalstimulation, for example using the parameters for rhythmic vagalstimulation described hereinabove.

In addition, in some cases adverse effects of the heart failure drug areprevented or diminished by allowing the use of lower dosages of the drugbecause of the synergistic effect of the vagal stimulation with the drugtreatment.

In an embodiment of the present invention, a method for enhancing orsustaining the efficacy of antithrombotic therapy comprisesadministering an antithrombotic drug to patient 30 and applying signalsto vagus nerve 24 that innervates heart 28 of the patient. The signalsare configured so as to increase atrial motion, which typically resultsin a synergistic effect between the therapeutic benefit of the drug andthe vagal stimulation. Such vagal stimulation thus may (a) increase theefficacy of the antithrombotic drug, and/or (b) allow the use of a lowerdosage of the drug, without reducing the efficacy of the drug. As usedin the present patent application including the claims, antithromboticdrugs are to be understood as drugs that are intended to reduce the riskof thromboembolic events, including, but not limited to, anticoagulationdrugs that inhibit the coagulation cascade (e.g., warfarin, heparin, lowmolecular weight heparin (LMWH)), and drugs that inhibit plateletaggregation (e.g., aspirin and clopidogrel). Increased efficacy causedby vagal stimulation may increase the effectiveness of a plateletaggregation inhibition drug, thereby allowing the use of such a druginstead of anticoagulation drugs, which typically have greater sideeffects and risks, and require more precise dosaging, than plateletaggregation inhibition drugs. In addition, use of a lower dosage mayreduce complications associated with typical dosages of antithromboticdrugs. For antithrombotic drug regimens in which dosages are selected toachieve a target international normalized ratio (INR) of 2.5, thesynergistic effect of the vagal stimulation with the drug treatment mayallow the same beneficial effect to be achieved at a lower INR, e.g.,1.5, thereby reducing drug complications. For some applications,antithrombotic therapy is enhanced or sustained by elevation of vagaltone and application of rhythmic synchronized vagal stimulation, forexample using the parameters for rhythmic vagal stimulation describedhereinabove.

In an embodiment of the present invention, vagal stimulation is appliedand configured to prevent atrial electrical remodeling caused by heartfailure (see the above-cited article by Li D et al.). For someapplications, such stimulation is applied to increase the efficacyand/or safety of a heart failure drug; for other applications, suchstimulation is applied in the absence of specific drug therapy. Suchprevention of electrical remodeling alone is believed by the inventorsto be therapeutically beneficial. In an embodiment, vagal stimulation isapplied and configured to treat a patient suffering from both AF andheart failure, such as by preventing atrial electrical remodeling,and/or by increasing the efficacy and/or safety of one or more drugs forAF and/or heart failure.

In an embodiment of the present invention, a method for enhancing theefficacy of drug treatment for heart failure comprises administering a“preload reduction” drug, such as an ACE inhibitor, nitrate, or sodiumnitroprusside, to patient 30, and applying signals to vagus nerve 24that innervates heart 28 of the patient. Such preload reduction drugsare intended to reduce the pressure in the venous system. During heartfailure, atrial contraction sometimes pushes blood back into the venousand pulmonary systems. To minimize this unwanted effect, the signalsapplied to the vagus nerve are configured so as to decrease atrialcontractile force, using the typical stimulation parameters describedhereinabove, for example with a short “on” time (e.g., between about 1and about 15 seconds) and a longer “off” time (e.g., between about 5 andabout 20 seconds). For some applications, the “on” and “off” times areequal, and for other applications, the “off” time is longer than the“on” time. In an embodiment, this vagal stimulation treatment is appliedwithout the preload reduction drug treatment.

In an embodiment of the present invention, a method for increasing vagaltone comprises applying signals to vagus nerve 24, and configuring thesignals to stimulate the vagus nerve, thereby delivering parasympatheticnerve stimulation to heart 28, while at the same time minimizing theheart-rate-lowering effects of the stimulation. Such treatment generallyresults in the beneficial effects of vagal stimulation that are notnecessarily dependent on the heart-rate reduction effects of suchstimulation. (See, for example, the above-cited article by Vanoli E etal.) Therefore, such vagal stimulation is generally useful for treatingconditions such as AF, heart failure, atherosclerosis, restenosis,myocarditis, cardiomyopathy, post-myocardial infarct remodeling, andhypertension. In addition, such treatment is believed by the inventorsto reduce the risk of sudden cardiac death in some patients (such asthose with hypertrophic cardiomyopathy or congenital long QT syndrome).Furthermore, such treatment is believed by the inventors to bebeneficial for the treatment of some non-cardiovascular conditions, suchas an autoimmune disease, an autoimmune inflammatory disease, multiplesclerosis, encephalitis, myelitis, immune-mediated neuropathy, myositis,dermatomyositis, polymyositis, inclusion body myositis, inflammatorydemyelinating polyradiculoneuropathy, Guillain Barre syndrome,myasthenia gravis, inflammation of the nervous system, SLE (systemiclupus erythematosus), rheumatoid arthritis, vasculitis, polyarteritisnodosa, Sjogren syndrome, mixed connective tissue disease,glomerulonephritis, thyroid autoimmune disease, sepsis, meningitis, abacterial infection, a viral infection, a fungal infection, sarcoidosis,hepatitis, and portal vein hypertension, obesity, constipation,irritable bowl syndrome, rheumatoid arthritis, glomerulonephritis,hepatitis, pancreatitis, thyroiditis, type I diabetes, and type IIdiabetes. For some applications, conditions mentioned in this paragraphare treated by applying vagal stimulation, and not necessarilyminimizing the heart-rate-lowering effects of the stimulation.

Such vagal stimulation is also beneficial for treating some conditionsor under some circumstances in which heart rate reduction is notindicated or is contraindicated. For example, such vagal stimulation istypically appropriate:

-   -   for treating heart failure patients that suffer from bradycardia        when taking beta-blockers;    -   at nighttime, when heart rate is naturally lower;    -   during exercise, such as when the heart rate is already within a        desired range and further decreases may reduce exercise        tolerance;    -   for patients receiving heart-rate lowering drugs, who have        achieved a heart rate within a desired range prior to beginning        vagal stimulation, and therefore would not benefit from further        heart rate reduction;    -   for patients suffering from low cardiac output, for whom heart        rate reduction may further reduce cardiac output;    -   during acute myocardial infarction with cardiogenic shock;    -   for patients who experience discomfort or a reduction in        exercise capacity when the heart rate is reduced; and    -   for patients having a tendency towards bradycardia when        receiving vagal stimulation.

In an embodiment of the present invention, in order to increase vagaltone while at the same time minimizing or preventing theheart-rate-lowering effects of the stimulation, control unit 32 appliesthe signals to the vagus nerve as a burst of pulses during each cardiaccycle, with one or more of the following parameters:

-   -   Timing of the stimulation: delivery of the burst of pulses        begins after a variable delay following each P-wave, the length        of the delay equal to between about two-thirds and about 90% of        the length of the patient's cardiac cycle. Such a delay is        typically calculated on a real-time basis by continuously        measuring the length of the patient's cardiac cycle.    -   Pulse duration: each pulse typically has a duration of between        about 200 microseconds and about 2.5 milliseconds for some        applications, or, for other applications, between about 2.5        milliseconds and about 5 milliseconds.    -   Pulse amplitude: the pulses are typically applied with an        amplitude of between about 0.5 and about 5 milliamps, e.g.,        about 1 milliamp.    -   Pulse repetition interval: the pulses within the burst of pulses        typically have a pulse repetition interval (the time from the        initiation of a pulse to the initiation of the following pulse)        of between about 2 and about 10 milliseconds, e.g., about 2.5        milliseconds.    -   Pulse period: the burst of pulses typically has a total duration        of between about 0.2 and about 40 milliseconds, e.g., about 1        millisecond.    -   Pulses per trigger (PPT): the burst of pulses typically contains        between about 1 and about 10 pulses, e.g., about 2 pulses.    -   Vagus nerve: the left vagus nerve is typically stimulated in        order to minimize the heart-rate-lowering effects of vagal        stimulation.    -   Duty cycle: stimulation is typically applied only once every        several heartbeats, or once per heartbeat, when a stronger        effect is desired.    -   On/off status: for some applications, stimulation is always        “on”, i.e., constantly applied (in which case, parameters closer        to the lower ends of the ranges above are typically used). For        other applications, on/off cycles vary between a few seconds to        several dozens of seconds, e.g., “on” for about 36 seconds,        “off” for about 120 seconds, “on” for about 3 seconds, “off” for        about 9 seconds.

For example, vagal stimulation may be applied to a patient having aheart rate of 60 BPM, with the intention of minimally reducing thepatient's heart rate. The burst of pulses may be delivered beginningabout 750 milliseconds after each R-wave of the patient. The stimulationmay be applied with one pulse per trigger (PPT), and having an amplitudeof 1 milliamp. The stimulation may be cycled between “on” and “off”periods, with each “on” period having a duration of about two seconds,i.e., two heart beats, and each “off” period having a duration of about4 seconds.

Alternatively or additionally, the control unit drives pacemaker 42 topace the heart, so as to prevent any heart-rate lowering effects of suchvagal stimulation. Typically, the control unit paces the heart at a ratethat is similar to the rate when the device is in “off” mode. Controlunit 32 then applies signals to vagus nerve 24, typically using thetypical stimulation parameters described hereinabove. This vagalstimulation generally does not lower the heart rate, because of thepacemaker pacing. For some applications, control unit 32 applies signalsto vagus nerve 24, and senses the heart rate after applying the signals.The control unit drives pacemaker 42 to pace the heart if the sensedheart rate falls below a threshold heart rate. The threshold heart rateis typically equal to a heart rate of the patient prior to commencingthe vagal stimulation, for example, as sensed by control unit 32. Thecontrol unit thus typically maintains the heart rate at a rate above abradycardia threshold rate, unlike conventional pacemakers which aretypically configured to pace the heart only when the rate falls below abradycardia threshold rate. Upon termination of vagal stimulation,control unit 32 typically drives pacemaker 42 to continue pacing theheart for a period typically having a duration between about 0 and about30 seconds, such as about 5 seconds.

In an embodiment of the present invention, control unit 32 drivespacemaker 42 to pace the heart, and configures the signals applied tothe vagus nerve using the typical stimulation parameters describedhereinabove. For some applications, the higher ends of the ranges ofvalues for one or more of these parameters are applied. The use of thepacemaker generally prevents any heart-rate-lowering effects of suchvagal stimulation.

In an embodiment of the present invention, control unit 32 appliesminimal-heart-rate-lowering stimulation using a feedback loop. Thecontrol unit calculates an average heart rate (ventricular and/or atrialrate) of the subject. The control unit then applies signals to vagusnerve 24, using the minimal heart rate reduction parameters describedhereinabove. During such stimulation, the control unit substantiallycontinuously monitors the resulting heart rate. If the heart ratedeclines by more than a certain percentage (e.g., by more than about 5%,such as from 100 BPM to 90 BPM), the control unit adjusts thestimulation parameters in order to further minimize theheart-rate-lowering effect of the stimulation. For example, the controlunit may adjust the stimulation parameters by reducing the amplitude ofthe stimulation, changing the timing of the stimulation, reducing thefrequency of the stimulation, reducing the duration of each pulse,and/or reducing the duration of the stimulation period.

In an embodiment of the present invention, a method for preventing orreducing fibrosis and/or inflammation of the heart comprises configuringcontrol unit 32 to apply signals to vagus nerve 24 that innervates heart28 of the patient. Substantially continuous application of suchstimulation generally modulates immune system responses, therebyreducing atrial, ventricular, and/or coronary inflammation and/orfibrosis. Such stimulation is typically applied using the typicalstimulation parameters described hereinabove, or the parametersdescribed hereinabove for minimal heart rate reduction. For someapplications, such stimulation is applied for more than about threeweeks. Conditions that are believed to be at least partiallyimmune-modulated, and therefore to generally benefit from such vagalstimulation, include, but are not limited to, atrial and ventricularremodeling (e.g., induced by AF, heart failure, myocarditis, and/ormyocardial infarct), restenosis, and atherosclerosis.

In an embodiment of the present invention, control unit 32 isconfiguring to apply signals to vagus nerve 24 of patient 30, and thesignals are configured to inhibit propagation of naturally-generatedefferent action potentials in the vagus nerve. Typically, the signalsare additionally configured to inhibit no more than about 10% ofnaturally-generated afferent action potentials traveling through thevagus nerve. It is hypothesized by the inventors that such inhibition isuseful for treating AF, typically by enhancing drug efficacy, and forpreventing bradycardia.

In an embodiment of the present invention, electrical signals areapplied by electrode device 22, typically on a long-term basis, to vagusnerve 24 of a subject not necessarily suffering from a heart condition,in order to increase the life expectancy, quality of life, and/orhealthiness of the subject. Such signals are typically configured to notreduce the heart rate below normal range for a typical human. Typicalparameters of such stimulation include those described hereinabove forminimal heart-rate-reducing stimulation, for periods during which theheart rate is at a desired level, and those described hereinabove forlowering heart rate, when it is desired to lower the heart rate fromabove normal to normal. For some applications, a determination regardingwhether to attempt to lower the heart rate is made responsive tophysiological parameters sensed using a sensor, such as an activitysensor, a respiration sensor, or accelerometer 39. Such chronic vagalstimulation is hypothesized by the inventors to be effective forincreasing life expectancy, quality of life, and/or healthiness by (a)causing a reduction in cardiovascular disease and/or events, (b) havingan anti-inflammatory effect, (c) reducing heart rate from faster thandesirable to desirable normal rates, (d) reducing metabolic rate, and/or(e) generally having a calming and relaxing effect.

For many of the applications of vagal stimulation described herein,electrode device 22 typically comprises one or more electrodes, such asmonopolar, bipolar or tripolar electrodes. Electrode device 22 istypically placed: (a) around vagus nerve 24, (b) around vagus nerve 24and the carotid artery (configuration not shown), or (c) inside thecarotid artery in a position suitable for vagal stimulation (not shown).Depending on the particular application, one or more electrode devices22 may be positioned to stimulate the left or right vagus nerve, eitherabove or below the cardiac branch bifurcation. For some applications,the electrodes comprise cuff electrodes, ring electrodes, and/or pointelectrodes. Typically, the electrodes stimulate the nerve without comingin direct contact therewith, by applying an electrical field to thenerve. Alternatively, the electrodes stimulate the nerve by coming indirect contact therewith. Control unit 32 typically configures thesignals to induce the propagation of efferent nerve impulses towardsheart 28.

In some embodiments of the present invention, when configuring vagalstimulation to induce the propagation of efferent nerve impulses towardsheart 28, control unit 32 drives electrode device 22 to (a) applysignals to induce the propagation of efferent nerve impulses towardsheart 28, and (b) suppress artificially-induced afferent nerve impulsestowards a brain 35 of the patient (FIG. 1), in order to minimizeunintended side effects of the signal application.

FIG. 2A is a simplified cross-sectional illustration of agenerally-cylindrical electrode device 22 applied to vagus nerve 24, inaccordance with an embodiment of the present invention. Electrode device22 comprises a central cathode 46 for applying a negative current(“cathodic current”) in order to stimulate vagus nerve 24, as describedbelow. Electrode device 22 additionally comprises a set of one or moreanodes 44 (44 a, 44 b, herein: “efferent anode set 44”), placed betweencathode 46 and the edge of electrode device 22 closer to heart 28 (the“efferent edge”). Efferent anode set 44 applies a positive current(“efferent anodal current”) to vagus nerve 24, for blocking actionpotential conduction in vagus nerve 24 induced by the cathodic current,as described below. Typically, electrode device 22 comprises anadditional set of one or more anodes 45 (45 a, 45 b, herein: “afferentanode set 45”), placed between cathode 46 and the edge of electrodedevice 22 closer to brain 35. Afferent anode set 45 applies a positivecurrent (“afferent anodal current”) to vagus nerve 24, in order to blockpropagation of action potentials in the direction of the brain duringapplication of the cathodic current.

For some applications, the one or more anodes of efferent anode set 44are directly electrically coupled to the one or more anodes of afferentanode set 45, such as by a common wire or shorted wires providingcurrent to both anode sets, substantially without any intermediaryelements. Typically, the sizes of the anodes and/or distances of thevarious anodes from the nerve are regulated so as to produce desiredratios of currents delivered through the various anodes. In theseapplications, central cathode 46 is typically placed closer to one ofthe anode sets than to the other, for example, so as to induceasymmetric stimulation (i.e., not necessarily unidirectional in allfibers) between the two sides of the electrode device. The closer anodeset typically induces a stronger blockade of the cathodic stimulation.

Cathode 46 and anode sets 44 and 45 (collectively, “electrodes”) aretypically mounted in a housing such as an electrically-insulating cuff48 and separated from one another by insulating elements such asprotrusions 49 of the cuff. Typically, the width of the electrodes isbetween about 0.5 and about 2 millimeters, or is equal to approximatelyone-half the radius of the vagus nerve. The electrodes are typicallyrecessed so as not to come in direct contact with vagus nerve 24. Forsome applications, such recessing enables the electrodes to achievegenerally uniform field distributions of the generated currents and/orgenerally uniform values of the activation function defined by theelectric potential field in the vicinity of vagus nerve 24.Alternatively or additionally, protrusions 49 allow vagus nerve 24 toswell into the canals defined by the protrusions, while still holdingthe vagus nerve centered within cuff 48 and maintaining a rigidelectrode geometry. For some applications, cuff 48 comprises additionalrecesses separated by protrusions, which recesses do not contain activeelectrodes. Such additional recesses accommodate swelling of vagus nerve24 without increasing the contact area between the vagus nerve and theelectrodes. For some applications, the distance between the electrodesand the axis of the vagus nerve is between about 1 and about 4millimeters, and is greater than the closest distance from the ends ofthe protrusions to the axis of the vagus nerve. Typically, protrusions49 are relatively short (as shown). The distance between the ends ofprotrusions 49 and the center of the vagus nerve is typically betweenabout 1 and 3 millimeters. (Generally, the diameter of the vagus nerveis between about 2 and 3 millimeters). Alternatively, for someapplications, protrusions 49 are longer and/or the electrodes are placedcloser to the vagus nerve in order to reduce the energy consumption ofelectrode device 22.

In an embodiment of the present invention, efferent anode set 44comprises a plurality of anodes 44, typically two anodes 44 a and 44 b,spaced approximately 0.5 to 2.0 millimeters apart. Application of theefferent anodal current in appropriate ratios from the plurality ofanodes generally minimizes the “virtual cathode effect,” wherebyapplication of too large an anodal current stimulates rather than blocksfibers. In an embodiment, anode 44 a applies a current with an amplitudeequal to about 0.5 to about 5 milliamps (typically one-third of theamplitude of the current applied by anode 44 b).

Anode 44 a is typically positioned in cuff 48 to apply current at thelocation on vagus nerve 24 where the virtual cathode effect is maximallygenerated by anode 44 b. For applications in which the blocking currentthrough anode 44 b is expected to vary substantially, efferent anode set44 typically comprises a plurality of virtual-cathode-inhibiting anodes44 a, one or more of which is activated at any time based on theexpected magnitude and location of the virtual cathode effect.

Likewise, afferent anode set 45 typically comprises a plurality ofanodes 45, typically two anodes 45 a and 45 b, in order to minimize thevirtual cathode effect in the direction of the brain. In certainelectrode configurations, cathode 46 comprises a plurality of cathodesin order to minimize the “virtual anode effect,” which is analogous tothe virtual cathode effect.

FIG. 2B is a simplified perspective illustration of electrode device 22,in accordance with an embodiment of the present invention. When appliedto vagus nerve 24, electrode device 22 typically encompasses the nerve.As described, control unit 32 typically drives electrode device 22 to(a) apply signals to vagus nerve 24 in order to induce the propagationof efferent action potentials towards heart 28, and (b) suppressartificially-induced afferent action potentials towards brain 35. Theelectrodes typically comprise ring electrodes adapted to apply agenerally uniform current around the circumference of the nerve, as bestshown in FIG. 2B.

FIG. 3 is a simplified perspective illustration of a multipolar pointelectrode device 140 applied to vagus nerve 24, in accordance with anembodiment of the present invention. In this embodiment, anodes 144 aand 144 b and a cathode 146 typically comprise point electrodes(typically 2 to 100), fixed inside an insulating cuff 148 and arrangedaround vagus nerve 24 so as to selectively stimulate nerve fibersaccording to their positions inside the nerve. In this case, techniquesdescribed in the above-cited articles by Grill et al., Goodall et al.,and/or Veraart et al. may be used. The point electrodes typically have asurface area between about 0.01 mm2 and 1 mm2. In some applications, thepoint electrodes are in contact with vagus nerve 24, as shown, while inother applications the point electrodes are recessed in cuff 148, so asnot to come in direct contact with vagus nerve 24, similar to therecessed ring electrode arrangement described above with reference toFIG. 2A. For some applications, one or more of the electrodes, such ascathode 146 or anode 144 a, comprise a ring electrode, as described withreference to FIG. 2B, such that electrode device 140 comprises both ringelectrode(s) and point electrodes (configuration not shown).Additionally, electrode device 22 optionally comprises an afferent anodeset (positioned like anodes 45 a and 45 b in FIG. 2A), the anodes ofwhich comprise point electrodes and/or ring electrodes.

Alternatively, ordinary, non-cuff electrodes are used, such as when theelectrodes are placed on the epicardial fat pads instead of on the vagusnerve.

FIG. 4 is a conceptual illustration of the application of current tovagus nerve 24 in order to achieve smaller-to-larger diameter fiberrecruitment, in accordance with an embodiment of the present invention.When inducing efferent action potentials towards heart 28, control unit32 drives electrode device 22 to selectively recruit nerve fibersbeginning with smaller-diameter fibers and to progressively recruitlarger-diameter fibers as the desired stimulation level increases. Thissmaller-to-larger diameter recruitment order mimics the body's naturalorder of recruitment.

Typically, in order to achieve this recruitment order, the control unitstimulates myelinated fibers essentially of all diameters using cathodiccurrent from cathode 46, while simultaneously inhibiting fibers in alarger-to-smaller diameter order using efferent anodal current fromefferent anode set 44. For example, FIG. 4 illustrates the recruitmentof a single, smallest nerve fiber 56, without the recruitment of anylarger fibers 50, 52 and 54. The depolarizations generated by cathode 46stimulate all of the nerve fibers shown, producing action potentials inboth directions along all the nerve fibers. Efferent anode set 44generates a hyperpolarization effect sufficiently strong to block onlythe three largest nerve fibers 50, 52 and 54, but not fiber 56. Thisblocking order of larger-to-smaller diameter fibers is achieved becauselarger nerve fibers are inhibited by weaker anodal currents than aresmaller nerve fibers. Stronger anodal currents inhibit progressivelysmaller nerve fibers. When the action potentials induced by cathode 46in larger fibers 50, 52 and 54 reach the hyperpolarized region in thelarger fibers adjacent to efferent anode set 44, these action potentialsare blocked. On the other hand, the action potentials induced by cathode46 in smallest fiber 56 are not blocked, and continue travelingunimpeded toward heart 28. Anode pole 44 a is shown generating lesscurrent than anode pole 44 b in order to minimize the virtual cathodeeffect in the direction of the heart, as described above.

When desired, in order to increase the parasympathetic stimulationdelivered to the heart, the number of fibers not blocked isprogressively increased by decreasing the amplitude of the currentapplied by efferent anode set 44. The action potentials induced bycathode 46 in the fibers now not blocked travel unimpeded towards theheart. As a result, the parasympathetic stimulation delivered to theheart is progressively increased in a smaller-to-larger diameter fiberorder, mimicking the body's natural method of increasing stimulation.Alternatively or additionally, in order to increase the number of fibersstimulated, while simultaneously decreasing the average diameter offibers stimulated, the amplitudes of the currents applied by cathode 46and efferent anode set 44 are both increased (thereby increasing boththe number of fibers stimulated and number of fibers blocked). Inaddition, for any given number of fibers stimulated (and not blocked),the amount of stimulation delivered to the heart can be increased byincreasing the PPT, frequency, and/or pulse width of the current appliedto vagus nerve 24.

In order to suppress artificially-induced afferent action potentialsfrom traveling towards the brain in response to the cathodicstimulation, control unit 32 typically drives electrode device 22 toinhibit fibers 50, 52, 54 and 56 using afferent anodal current fromafferent anode set 45. When the afferent-directed action potentialsinduced by cathode 46 in all of the fibers reach the hyperpolarizedregion in all of the fibers adjacent to afferent anode set 45, theaction potentials are blocked. Blocking these afferent action potentialsgenerally minimizes any unintended side effects, such as undesired orcounterproductive feedback to the brain, that might be caused by theseaction potentials. Anode 45 b is shown generating less current thananode 45 a in order to minimize the virtual cathode effect in thedirection of the brain, as described above.

In an embodiment of the present invention, the amplitude of the cathodiccurrent applied in the vicinity of the vagus nerve is between about 2milliamps and about 10 milliamps. Such a current is typically used inembodiments that employ techniques for achieving generally uniformstimulation of the vagus nerve, i.e., stimulation in which thestimulation applied to fibers on or near the surface of the vagus nerveis generally no more than about 400% greater than stimulation applied tofibers situated more deeply in the nerve. This corresponds tostimulation in which the value of the activation function at fibers onor near the surface of the vagus nerve is generally no more than aboutfour times greater than the value of the activation function at fiberssituated more deeply in the nerve. For example, as described hereinabovewith reference to FIG. 2A, the electrodes may be recessed so as not tocome in direct contact with vagus nerve 24, in order to achievegenerally uniform values of the activation function. Typically, but notnecessarily, embodiments using approximately 5 mA of cathodic currenthave the various electrodes disposed approximately 0.5 to 2.5 mm fromthe axis of the vagus nerve. Alternatively, larger cathodic currents(e.g., 10-30 mA) are used in combination with electrode distances fromthe axis of the vagus nerve of greater than 2.5 mm (e.g., 2.5-4.0 mm),so as to achieve an even greater level of uniformity of stimulation offibers in the vagus nerve.

In an embodiment of the present invention, the cathodic current isapplied by cathode 46 with an amplitude sufficient to induce actionpotentials in large- and medium-diameter fibers 50, 52, and 54 (e.g., A-and B-fibers), but insufficient to induce action potentials insmall-diameter fibers 56 (e.g., C-fibers). Simultaneously, an anodalcurrent is applied by anode 44 b in order to inhibit action potentialsinduced by the cathodic current in the large-diameter fibers (e.g.,A-fibers). This combination of cathodic and anodal current generallyresults in the stimulation of medium-diameter fibers (e.g., B-fibers)only. At the same time, a portion of the afferent action potentialsinduced by the cathodic current are blocked by anode 45 a, as describedabove. Alternatively, the afferent anodal current is configured to notfully block afferent action potentials, or is simply not applied. Inthese cases, artificial afferent action potentials are neverthelessgenerally not generated in C-fibers, because the applied cathodiccurrent is not strong enough to generate action potentials in thesefibers.

These techniques for efferent stimulation of only B-fibers are typicallyused in combination with techniques described hereinabove for achievinggenerally uniform stimulation of the vagus nerve. Such generally uniformstimulation enables the use of a cathodic current sufficiently weak toavoid stimulation of C-fibers near the surface of the nerve, while stillsufficiently strong to stimulate B-fibers, including B-fibers situatedmore deeply in the nerve, i.e., near the center of the nerve. For someapplications, when employing such techniques for achieving generallyuniform stimulation of the vagus nerve, the amplitude of the cathodiccurrent applied by cathode 46 may be between about 3 and about 10milliamps, and the amplitude of the anodal current applied by anode 44 bmay be between about 1 and about 7 milliamps.

For some applications, control unit 32 is adapted to receive feedbackfrom one or more of the electrodes in electrode device 22, and toregulate the signals applied to the electrode device responsive thereto.For example, control unit 32 may analyze amplitudes of various peaks ina compound action potential (CAP) signal recorded by the electrodes, inorder to determine a relative proportion of stimulated larger fibers(having faster conduction velocities) to smaller fibers (having slowerconduction velocities). Alternatively or additionally, control unit 32analyzes an area of the CAP, in order to determine an overall effect ofthe stimulation. In an embodiment, the feedback is received byelectrodes other than those used to apply signals to the nerve.

FIG. 5 is a simplified illustration of an ECG recording 70 and exampletimelines 72 and 76 showing the timing of the application of a burst ofstimulation pulses 74, in accordance with an embodiment of the presentinvention. The application of the burst of pulses in each cardiac cycletypically commences after a variable delay after a detected R-wave,P-wave, or other feature of an ECG. For some applications, otherparameters of the applied burst of pulses are also varied in real time.Such other parameters include amplitude, pulses per trigger (PPT), pulseduration, and pulse repetition interval. For some applications, thedelay and/or one or more of the other parameters are calculated in realtime using a function, the inputs of which include one or morepre-programmed but updateable constants and one or more sensedparameters, such as the R-R interval between cardiac cycles and/or theP-R interval.

The variable delay before applying pulse burst 74 in each cardiac cyclecan be measured from a number of sensed physiological parameters(“initiation physiological parameters”), including sensed points in thecardiac cycle, including P-, Q-, R-, S- and T-waves. Typically the delayis measured from the P-wave, which indicates atrial contraction.Alternatively, the delay is measured from the R-wave, particularly whenthe P-wave is not easily detected. Timeline A 72 and Timeline B 76 showthe delays, dt_(R) and dt_(P) measured from R and P, respectively.

In an embodiment, a lookup table of parameters, such as delays (e.g.,dt) and/or other parameters, is used to determine in real time theappropriate parameters for each application of pulses, based on the oneor more sensed parameters, and/or based on a predetermined sequencestored in the lookup table.

Optionally, the stimulation applied by vagal stimulation apparatus 20 isapplied in conjunction with or separately from stimulation ofsympathetic nerves innervating the heart. For example, vagal inhibitiondescribed herein and/or periods of non-stimulation of the vagus nervedescribed herein may be replaced or supplemented by excitation ofsympathetic nerves. Such sympathetic stimulation can be applied usingtechniques of smaller-to-larger diameter fiber recruitment, as describedherein, or other nerve stimulation techniques known in the art. For someapplications, vagal stimulation is applied in conjunction withstimulation of sympathetic nerves in order to increase vagal tone whileminimizing the heart-rate-lowering effect of the vagal stimulation.

Alternatively or additionally, the techniques of smaller-to-largerdiameter fiber recruitment are applied in conjunction with methods andapparatus described in one or more of the patents, patent applications,articles and books cited herein.

Reference is now made to FIG. 6, which is a graph showing in vivoexperimental results measured in accordance with an embodiment of thepresent invention. A SABAR white rat, weighing 350 g, was anesthetizedwith Phenobarbital; no other medications were administered. Vagalstimulation was applied using a silver chloride hook electrode immersedin oil placed over the right vagus nerve.

The graph of FIG. 6 shows change in heart rate vs. baseline heart rate,as measured over a 300 second period. During the entire period of theexperiment, vagal stimulation was applied in 500 microsecond pulseshaving an amplitude of 4 mA, at a frequency of 8 Hz. The stimulation wasnot synchronized with the cardiac cycle of the animal. Beginning at 0seconds, and concluding at about 12 seconds, 0.8 mg per kg body weightof atropine was administered by intravenous injection to the tail vein.

During the approximately 12 seconds of atropine administration, prior tothe atropine taking effect, vagal stimulation is seen demonstrating itsexpected heart-rate lowering effect, which is attributable to theparasympathetic effect of such stimulation. However, beginning atapproximately 13 seconds, with the onset of the effectiveness of theatropine, the heart rate suddenly increased to a level that variedbetween about 0 and about 20 beats per minute greater than baselineheart rate. This increase is attributed to the fact that vagalstimulation generally has both a parasympathetic and adrenergic effect.Under normal circumstances, the parasympathetic effect dominates theadrenergic effect. However, when the parasympathetic effect is blocked,such as by atropine, the adrenergic effect is expressed, resulting inincreased heart rate, among other effects. Beginning at about 180seconds, as the atropine-induced parasympathetic blockade faded, theparasympathetic effect of stimulation again began to dominate, resultingin a reduced heart rate.

It is believed by the inventors that these experimental results at leastin part explain the effectiveness of the minimal heart rate reductionstimulation described hereinabove. During stimulation with suchparameters, the heart-rate-lowering effects of vagal stimulation arenearly offset by the adrenergic effects of the vagal stimulation.Nevertheless, the parasympathetic nervous system is still activated,resulting in the beneficial effects of such stimulation describedhereinabove.

FIG. 7 is a graph showing in vivo experimental results measured inaccordance with an embodiment of the present invention. A male dog,weighing 25 kg, was initially anesthetized with propafol; anesthesia wasmaintained with inhaled gas isoflurane. The dog was mechanicallyventilated. The right vagus nerve was stimulated using a tripolar cuffelectrode in an anode-cathode-anode configuration, with the anodesshorted to each other, similar to the shorted anode configurationdescribed hereinabove with reference to FIG. 2A. The cuff electrode wasimmersed in normal saline solution.

The graph of FIG. 7 shows heart rate reduction vs. baseline (withreduction expressed by positive values) responsive to vagal stimulationapplied after different delays from the R-wave. Baseline heart rate wascalculated based on the average interval between beats prior tobeginning stimulation. For each data point, the heart rate wascalculated as the time interval between the second and third beat afterapplication of the stimulation. The reduction in heart rate caused bythe stimulation is shown on the y-axis. As is seen in the graph, longerdelays from the R-wave generally resulted in less heart rate reduction.Delays of at least 200 milliseconds resulted in substantially noreduction in heart rate. It is believed by the inventors that these datasupport the timing parameters of the minimal heart rate reductionstimulation described hereinabove. It is hypothesized by the inventorsthat for each of the delays shown, total acetylcholine release issubstantially the same. In support of this hypothesis, it is noted thatacetylcholine is released in efferent fibers in response to the appliedvagal stimulation, but is expected to be largely (or entirely)unaffected in these fibers by the precise timing of the cardiac cycle,because these fibers do not receive input from the heart. Becauseacetylcholine release is an indication of the level of parasympatheticstimulation, this hypothesis as well as the experimental resultsindicate that vagal stimulation, with delays chosen in accordance withthis embodiment, has little or no effect on heart rate, whilemaintaining substantially the same effect on the parasympathetic nervoussystem.

In an embodiment of the present invention, a calibration period isprovided to determine a delay for each patient that generallycorresponds to, for example, the 200 ms delay shown in the figure, andthis determined delay is applied to allow vagal stimulation with minimalheart rate reduction in the patient.

FIG. 8 is a chart showing in vivo experimental results in accordancewith an embodiment of the present invention. A SABAR white rat, weighing350 g, was anesthetized with Phenobarbital. Vagal stimulation wasapplied using a silver chloride hook electrode immersed in oil placedover the right vagus nerve. Vagal stimulation was applied with anamplitude of 1.5 milliamps. Medications, as described below, wereadministered intravenously through the tail vein.

The chart of FIG. 8 shows heart rate reductions vs. baseline heart rates(with the reductions expressed by positive values) responsive to vagalstimulation applied alone (bars 1), vagal stimulation applied afteradministration of 1 mg of the beta-blocker metoprolol (bars 2), andvagal stimulation applied after administration of 0.2 mg of adrenaline(bars 3). (For determining the metoprolol and adrenaline reductions, therespective baselines were measured after the medications had takeneffect). The left bar in each pair of bars shows results when vagalstimulation was synchronized with the cardiac cycle, and the right barshows results with unsynchronized stimulation. As is seen, both thebeta-blocker and adrenaline cause vagal stimulation to achieve a greaterheart-rate-lowering effect at the same level of stimulation.

FIGS. 9A and 9B are graphs showing an analysis of the experimentalresults of the experiment described hereinabove with reference to FIG.7, in accordance with an embodiment of the present invention. Bothgraphs show heart rate reduction vs. baseline (with reduction expressedby positive values). However, in FIG. 9A increased reduction wasachieved by increasing the amplitude of the applied signal, while inFIG. 9B increased reduction was achieved by increasing the number ofpulses per trigger (PPT), i.e., the number of pulses in a pulse trainapplied once per cardiac cycle. The pulses of the experiment shown inFIG. 9B were applied after a constant delay of 60 ms after each R-wave,synchronized with the cardiac cycle.

Although similar fine control of heart rate reduction was achieved usingmodulation of both parameters, the animal experienced severe sideeffects, including breathing difficulties (gasping, belching,hoarseness, and wheezing), when signal amplitude was modulated (FIG. 9A)and the heart rate reduction reached about 40 beats per minute.Substantially no side effects were observed when PPT was modulated.These data suggest that heart rate reduction can be achieved with fewerside effects by varying PPT rather than signal amplitude.

FIGS. 10A and 10B are graphs showing in vivo experimental results inaccordance with an embodiment of the present invention. These graphsrespectively reflect two different sets of parameters used to achievevagal stimulation with minimal heart-rate-lowering effects. A SABARwhite rat, weighing 350 g, was anesthetized with Phenobarbital; no othermedications were administered. Vagal stimulation was applied using asilver chloride hook electrode immersed in oil placed over the rightvagus nerve. The heart rate in FIG. 10A is expressed as a percent changefrom a baseline average heart rate.

The data shown in the graph of FIG. 10A were obtained using thefollowing stimulation parameters: (a) an “on” time of 12.5 seconds (10triggers), and an “off” time of 110 seconds, (b) 1 pulse per trigger,(c) a stimulation frequency of 0.8 Hz, (d) an amplitude of 2 milliamps,and (e) a pulse width of 500 microseconds. Stimulation was appliedbetween about 336 and about 348.5 seconds. As seen in the graph, thestimulation initially reduced the heart rate (until about 350 seconds).However, upon cessation of stimulation at 348.5 seconds, heart rateincreased with rebound strength for about 40 seconds (until about 390seconds). As a result, the average heart rate caused by stimulation wasnot substantially different from the average heart rate withoutstimulation. This lack of substantial difference is illustrated by thetwo horizontal lines of the graph. The upper line represents the averageheart rate during stimulation and the 40 seconds following stimulation(i.e., between 330 and 390 seconds), while the lower line represents theaverage heart rate excluding these periods (i.e., the average heart ratebetween 300 and 330 seconds, and between 390 and 420 seconds.

The data shown in the graph of FIG. 10B were obtained using thefollowing stimulation parameters: (a) 1 pulse per trigger, (b) anamplitude of 0.1 mA, and (c) a pulse duration of 500 microseconds.Stimulation was applied at two stimulation time points, the first at 35seconds and the second at 100 seconds. The stimulation applied at thefirst point consisted of 4 triggers (i.e., cardiac cycles), while thestimulation applied at the second point consisted of 12 triggers. As isshown on the graph, the stimulation applied at the first point hadessentially no heart-rate-lowering effect, while the stimulation appliedat the second point substantially lowered the heart rate. These resultsdemonstrate that, mutatis mutandis, the heart-rate-lowering effect ofvagal stimulation depends in part upon the length (i.e., number oftriggers) of the stimulation. By using a brief stimulation period, vagalstimulation can be achieved while having a minimal or noheart-rate-lowering effect.

Although some embodiments of the present invention are described hereinwith respect to applying an electrical current to tissue of a patient,this is to be understood in the specification and in the claims asincluding creating a voltage drop between two or more electrodes.

Although embodiments of the present invention described hereinabove withreference to FIGS. 2A, 2B, 3 and 4 are described with reference to thevagus nerve, the electrode devices of these embodiments may also beapplied to other nerves for some applications.

As appropriate, techniques described herein are practiced in conjunctionwith methods and apparatus described in one or more of the followingpatent applications, all of which are assigned to the assignee of thepresent application and are incorporated herein by reference:

-   -   U.S. patent application Ser. No. 10/205,474, filed Jul. 24,        2002, entitled, “Electrode assembly for nerve control,” which        published as US Patent Publication 2003/0050677    -   U.S. Provisional Patent Application 60/383,157 to Ayal et al.,        filed May 23, 2002, entitled, “Inverse recruitment for autonomic        nerve systems”    -   U.S. patent application Ser. No. 10/205,475, filed Jul. 24,        2002, entitled, “Selective nerve fiber stimulation for treating        heart conditions,” which published as US Patent Publication        2003/0045909    -   PCT Patent Application PCT/IL02/00068, filed Jan. 23, 2002,        entitled, “Treatment of disorders by unidirectional nerve        stimulation,” and U.S. patent application Ser. No. 10/488,334,        filed Feb. 27, 2004, in the US National Phase thereof    -   U.S. patent application Ser. No. 09/944,913, filed Aug. 31,        2001, entitled, “Treatment of disorders by unidirectional nerve        stimulation”    -   U.S. patent application Ser. No. 10/461,696, filed Jun. 13,        2003, entitled, “Vagal stimulation for anti-embolic therapy”    -   PCT Patent Application PCT/IL03/00430, filed May 23, 2003,        entitled, “Electrode assembly for nerve control,” which        published as PCT Publication WO 03/099373    -   PCT Patent Application PCT/IL03/00431, filed May 23, 2003,        entitled, “Selective nerve fiber stimulation for treating heart        conditions,” which published as PCT Publication WO 03/099377    -   U.S. patent application Ser. No. 10/719,659, filed Nov. 20,        2003, entitled, “Selective nerve fiber stimulation for treating        heart conditions”    -   A PCT patent application filed May 23, 2004, entitled,        “Selective nerve fiber stimulation for treating heart        conditions”    -   A PCT patent application filed on even date herewith, entitled,        “Vagal stimulation for anti-embolic therapy”

It will be appreciated by persons skilled in the art that the presentinvention is not limited to what has been particularly shown anddescribed hereinabove. Rather, the scope of the present inventionincludes both combinations and subcombinations of the various featuresdescribed hereinabove, as well as variations and modifications thereofthat are not in the prior art, which would occur to persons skilled inthe art upon reading the foregoing description.

1. A method comprising: administering, to a subject susceptible to bradycardia, a beta-blocker at a dosage lower than would normally be indicated for the subject; applying a current to a site of the subject selected from the group of sites consisting of: a vagus nerve of the subject, an epicardial fat pad of the subject, a pulmonary vein of the subject, a carotid artery of the subject, a carotid sinus of the subject, a vena cava vein of the subject, and an internal jugular vein of the subject; sensing a heart rate of the subject; and upon detecting an occurrence of the bradycardia, terminating applying the current at least until a cessation of the bradycardia.
 2. The method according to claim 1, wherein applying the current comprises applying the current in respective bursts of pulses in each of a plurality of cardiac cycles of the subject.
 3. The method according to claim 2, wherein applying the current comprises synchronizing the bursts with a cardiac cycle of the subject.
 4. The method according to claim 2, wherein applying the current comprises applying a first pulse of each of the bursts after a delay from a sensed feature of an electrocardiogram (ECG) of the subject.
 5. The method according to claim 2, wherein applying the current comprises configuring each of the pulses to have a duration of between about 100 microseconds and about 2.5 milliseconds.
 6. The method according to claim 1, wherein applying the current comprises configuring the current so as to have an antiarrhythmic effect on an atrium of the subject.
 7. The method according to claim 1, wherein applying the current comprises configuring the current to inhibit propagation of naturally-generated efferent action potentials traveling through the site.
 8. The method according to claim 7, wherein applying the current comprises applying the current to the vagus nerve.
 9. The method according to claim 1, wherein the subject suffers from heart failure, and wherein administering comprises administering the beta-blocker to the subject suffering from the heart failure.
 10. The method according to claim 1, wherein applying the current comprises configuring the current at least in part responsively to the sensed heart rate.
 11. The method according to claim 1, wherein applying the current comprises configuring one or more parameters of the current so as to minimize a heart-rate-lowering effect of the applying of the current. 